Mechanism of Tubulointerstitial Fibrosis

BRIEF REVIEW
www.jasn.org
Mechanisms of Tubulointerstitial Fibrosis

Michael Zeisberg* and Eric G. Neilson
*Division of Matrix Biology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts; and Departments of Medicine and Cell and Developmental Biology, Vanderbilt University School of Medicine, Nashville, Tennessee
ABSTRACT
The pathologic paradigm for renal progression is advancing tubulointerstitial fibrosis. Whereas mechanisms underlying fibrogenesis have grown in scope and understanding in recent decades, effective human treatment to directly halt or even reverse fibrosis remains elusive. Here, we examine key features mediating the molecular and cellular basis of tubulointerstitial fibrosis and highlight new insights that may lead to novel therapies. How to prevent chronic kidney disease from progressing to renal failure awaits even deeper biochemical understanding.
J Am Soc Nephrol 21: 1819 1834, 2010. doi: 10.1681/ASN.2010080793
Progressive tubulointerstitial fibrosis is the final common pathway for all kidney diseases leading to chronic renal failure.1,2 Its presence correlates with impaired excretory function1 and the degree of fibrosis3,4 or fibroblast number5 are robust pathologic markers of progression. The histopathology of tubulointerstitial fibrosis features deposition of interstitial matrix in association with inflammatory cells, tubular cell loss, fibroblast accumulation, and rarefaction of the peritubular microvasculature.6 There is broad agreement that each of these hallmarks contributes to relentless progression, although priority and interrelationship among the various components including their genetic predisposition are still muddled by unresolved complexity (Figure 1). Humans lose about 4500 nephrons per year per kidney,7 and although not all agree,8,9 classic inulin clearance studies suggest GFR falls by 10 ml/min per decade of life.10 Therefore, the calculus for conceptualizing normal loss of renal function over time begins with a starting number of nephrons at birth integrated by the natural history of tissue involution
J Am Soc Nephrol 21: 18191834, 2010
from a lifetime of subclinical vascular disease, metabolic stress, cicatrization, and nephrosclerosis;1114 hence, the privilege of aging provides a natural window into basic mechanisms of renal fibrogenesis. Aging disturbs normal structurefunction relationships in the kidney for many reasons,15,16 including the influence of telomere shortening on cell senescence,16 18 aberrant DNA methylation destabilizing the epigenome of renal cells,19 loss of self-renewing stem cells,20 22 and diminished rates of tubular cell proliferation.23 These nuclear consequences of aging are compounded by dysregulation of cellular energy sensors,24 oxidative stress,13,25,26 and mitochondrial dysfunction26,27 fogging the integrity of nephron structure with progressive glomerular and tubulointerstitial fibrosis.12,13,28 PPAR agonists attenuate some of these aging effects by engaging klotho,29 stabilizing mitochondrial deterioration,29 and reducing the activity of TGF,29,30 all to suggest that aging renal tissues are susceptible to the longitudinal affects of profibrotic signals.19,23,28,31 Persistent subclinical injury
to the tubulointerstitium also affects the normal physiology of many nephrons at once, which explains the sensitivity of GFR to the spread of pernicious fibrogenesis.1 Whereas the molecular mechanisms driving fibrogenesis are better understood from 20 years ago1 and a variety of preclinical strategies to inhibit or even reverse tubulointerstitial fibrosis are effective in rodents, only a few antifibrotic therapies are in clinical use today.2,3234 Finding better targets for future therapy in humans will require deeper understanding of the molecular signals modulating fibrogenic events.
THE EXTRACELLULAR MATRIX
Excessive deposition of extracellular matrix, particularly the presence of collagenous fibers, is the most striking and name-lending feature of tubulointerstitial fibrosis.6 By definition, fibrosis associates with both quantitative and qualitaPublished online ahead of print. Publication date available at www.jasn.org. Correspondence: Dr. Michael Zeisberg, Harvard Medical School, Division of Matrix Biology, Beth Israel Deaconess Medical Center, 330 Brookline Avenue, RW 736C, Boston, MA 02215. Phone: 617-667-3583; Fax: 617-667-0360; E-mail: mzeisber@bidmc.harvard.edu; or Dr. Eric G. Neilson, Departments of Medicine and Cell and Developmental Biology, D-3100 MCN, Vanderbilt University School of Medicine, Nashville, TN 37232-2358. Phone: 615-322-3146; Fax: 615-3439391; E-mail: eric.neilson@vanderbilt.edu Copyright 2010 by the American Society of Nephrology
ISSN : 1046-6673/2111-1819
1819
BRIEF REVIEW
www.jasn.org
Figure 1. Interactive relationships producing fibrosis. Renal fibrosis constitutively involves inflammation, fibroblast activation, injury to the tubular epithelium, and microvascular rarefaction. Our understanding of how inflammatory cells, fibroblasts, tubular epithelial cells (TECs), and endothelial cells actively contribute to fibrogenesis has evolved considerably during the past 20 years and sustained growth factor pressure within the microenvironment and increased susceptibility to growth factormediated stimulation emerge as the principal driving force of fibrosis. The molecular systems that determine choice between pathologic fibrosis and physiologic repair however are still evolving. Epidemiologic studies identify genetic polymorphisms, epigenetic modifications, and aging as risk factors for chronic kidney disease. Linking these risk factors mechanistically to fibrosis is a task for the future.
tive changes in matrix.1 In fibrotic kidneys the widened interstitial spaces fill with fibrillar material consisting of predominantly collagens type I and III and fibronectin.1,35 This fibrotic matrix also contains residual fragments of collagen type IV, which are normally found in basement membranes otherwise supporting intact endothelia or tubular epithelia36,37 as well as several fibronectin splice variants that modulate fibrogenic potential.38 The actual amount of collagen produced by renal fibrogenesis seems to attenuate fairly soon after it starts, whereas the relative extent of fibrosis seems to increase with time.39 This dynamic incongruity can be reconciled by recognizing that the volume of injured kidney also decreases as residual renal parenchyma collapses around invasive interstitial scars.40 Whereas fibrillar collagens spontaneously assemble in vitro, this is not what happens in vivo.41 During normal and abnormal tissue remodeling, interstitial collagens have numerous binding partners and those critical for fibrillar assembly include fibronectin, collagen type V, fibronectin and collagen-binding integrins, and various fibrillins, including latent TGF-binding proteins (LTBP).42,43 Prototypical matrix deposition follows a
1820
process where the initial appearance of collagen nucleators in interstitial fluid serve as scaffolding for fibrillar collagens produced by local fibroblasts.43 Fibronectin, collagen type V, LTBP, and secreted protein acidic and rich in cysteine (SPARC) are interactive regulators of this matrix assembly:42 44 fibronectin co-localizes with procollagen secretion to establish conformation-dependent relationships with 51 integrins on fibroblasts43 and collagen type V operates at the fibrillar core of collagen type I assembly.45 LTBPs facilitate the secretion of pro-TGF and provide a mechanism for its release and activation.42 SPARC is antiproliferative, 46 stimulates the expression of matrix metalloproteinases (MMPs)47 and plasminogen activator inhibitor-1 (PAI-1), 48 and activates integrin-linked kinase (ILK),46 which engages epithelial-mesenchymal (EMT) or endothelial-mesenchymal transitions (EndMT) producing fibroblasts. 49 51 All of these processes shape the collagenous matrix found in normal or disturbed tissues. Generally speaking, fibrogenesis initiates in small areas at random sites of inflammation and then expands to become diffuse if profibrotic drivers persist.52 The accumulation of fibroblasts in
these damaged tissues is linked to the risk of fibrosis.5 Unfortunately, it is difficult technically to assign a definitive secretory role for collagen to any particular cell type found in these fibrogenic hot spots, and consequently, most in vivo experiments rely on surrogate markers of collagen secretion such as in situ hybridization of mRNA encoding collagen chains,53 collagen promoter activity,54,55 or the presence of collagen-containing cells.56 Better still, the endoplasmic expression of the collagen type I chaperone, HSP47, seems more related to secretion,57 60 and cell-specific deletions that associate with decreased matrix accumulation strongly insinuate secretory function.61 Fibroblasts use collagen fibrils as scaffolding to crawl among damaged tissue planes, and mathematical modeling suggests that fibroblast number and movement depends on their sensitivity to chemoattractant diffusion.62 These gradients increase collagen alignment in fibrogenic tissue to facilitate the accrual of fibroblasts. The details of these events can be difficult to assess in tissues biochemically, as important modulators of phenotypic change, particularly cytokines, may express at levels not easily detectable, and in vitro activators or inhibitors may be artificially binary just by their presence in serum.63 However, the presence of PDGF and the absence of TGF and FGF2/bFGF in fetal wounds that do not scar compared with the presence of all three cytokines in adult tissue that do suggests differential expression patterns of key growth factors may be necessary for enduring fibrogenesis.63 Prototypical TGF signaling through Smad pathways64,65 under microRNA66 and epigenetic control67,68 has one of the strongest profibrotic effects on matrix production.69,70 The proximal action of angiotensin II as a morphogenic cytokine stimulating TGF71 and PAI-172 has also led to the well-known renoprotective effects of renin-angiotensin inhibition.2,73 Whereas containment of TGF signaling has been the centerpiece of various experimental antifibrotic therapies,74 80 knockdown of TGF type II receptors along the collecting duct paradoxically accelerates renal fibrosis associated with ureteral obstruction,81
J Am Soc Nephrol 21: 1819 1834, 2010
Journal of the American Society of Nephrology
www.jasn.org
BRIEF REVIEW
all to suggest that too much or too little of even a single cytokine may be profibrogenic.82
TISSUE PROTEASES
Removal of extracellular matrix from the interstitium hinges on a well-worn belief in the role of various endogenous proteases. Most studies in this area focus on two families of proteases: MMPs and members of the plasmin-dependent pathway. Both classes of proteases have the potential to fragment some extracellular matrix for removal, but also cleave nonmatrix substrates, releasing profibrotic growth factors that paradoxically trigger unwelcome consequences. MMPs are a family of zinc-dependent endopeptidases that currently includes 25 members with varying substrate specificities controlled by tissue inhibitors of metalloproteinases 1-4.83 The overlapping activity and specificity of MMPs make it difficult to dissect individual actions in vivo. Most studies in the kidney focus on MMP-2 and MMP-9 (both degrade collagen type IV84 and perhaps collagen types I and III85), but fail to demonstrate a consistent antifibrotic effect in the interstitium.86,87 For example, combined pharmacologic inhibition of MMP-2, MMP-3, and MMP-9 at advanced stages of disease in Alport mice accelerates renal fibrogenesis, whereas combined MMP inhibition before onset of tubulointerstitial fibrosis is protective.88 More confusing, studies utilizing MMP null mice show unaccelerated fibrogenesis, and overexpression of MMP-2 in tubular epithelial cells is sufficient to induce tubulointerstitial fibrosis.87 89 The profibrotic effects of MMP-2 and MMP-9 on renal fibrosis, particularly the activation of MMP-2 and MMP-14 (MT1-MMP) by TGF associated with the degradation of basement membrane stimulating EMT,87 seem to outweigh their antifibrotic potential; in fact, mice deficient in TIMP-3 spontaneous develop interstitial fibrosis.90 MMP-14, a membrane-bound activator of secreted MMP-2 and MMP-9 in fibroblasts, is critical for invasiveness into the interstiJ Am Soc Nephrol 21: 1819 1834, 2010
tial environment containing collagen types I and III85 and its expression is under the control of Snail, which is a key regulator of the EMT program.91,92 Thus, epithelial cells, engaged by TGF, express essential MMPs for both basement membrane degradation and interstitial invasion that are ultimately required for successful completion of EMT or detachment and loss into the tubular lumen (Figure 2). The effects of the plasminogen-plasmin system on fibrosis are equally complex. Active plasmin is derived from proteolytic cleavage of plasminogen by tissue-type plasminogen activator (tPA) or urokinase-type plasminogen activator (uPA), which in turn are inhibited by PAI-1.93 Plasmin degrades some matrix constituents, including laminin, entactin, perlecan, and fibronectin,93,94 whereas fibrillar collagen seems more resistant.95 Plasmin, perhaps more importantly, also affects cell behavior and function in the fibrotic environment and promotes fi-
brogenesis by activating MMPs96 and stimulating EMT.97 tPA null mice with ureteral obstruction have reduced local expression of MMP-9 and preserved tubular basement membrane with less EMT, and less interstitial fibrosis,98 whereas urokinase cellular receptor (uPAR) null mice develop worse renal fibrosis with lower expression levels of the antifibrotic cytokine, hepatocyte growth factor (HGF).99 Angiotensin II stimulates the PAI-1 promoter in tubular cells100 and tubulointerstitial fibrosis associates with TGF-stimulated PAI-1 expression,101 whereas the genetic deletion of PAI-1 ameliorates renal fibrogenesis in mice.72,102,103 The small heterodimer partner (SHP) represses the transcription of TGF/Smad3regulated PAI-1 expression, and SHP null mice develop more renal fibrosis, whereas SHP overexpression inhibits its development;101 SHP may turn out to be an interesting therapeutic candidate depending on its molecular specificity.
Figure 2. Tissue proteases and tubular decondensation. Whereas proteases are key modifiers of interstitial matrix, they also are critical for the disruption of basement membrane. Tubular epithelial cells receive signals from the microenvironment to change phenotype. As they release from basement membrane, they can either round up and fall into the tubular lumen or undergo epithelial-mesenchymal transition and invade the interstitium through rents in damaged basement membrane. SPARC through ILK, angiotensin II, and TGF activate nuclear programs (SHP, Snail1, and Smads) that engage in EMT-forming fibroblasts. Part of this mechanism is to stimulate the release of PAI-1, MMP-2, and MMP-9. MMP-2 and MMP-9 are activated by membrane-bound MMP-14, which is also modulated by PAI-1, tPA, and plasmin effects on MMPs.
1821
BRIEF REVIEW
www.jasn.org
The profibrotic action of these proteases is a paradigm shift in thinking about the dynamics of matrix deposition or its dissolution (Figure 2), illustrating the complexity of balancing modifier effects, timing and context, and weighing what seems to be true in vitro with what is not observed in vivo. Whereas current evidence argues against MMPs or plasmin to degrade only complex matrixes in vivo, murine studies reporting regression of tubulointerstitial fibrosis do demonstrate less matrix deposition.104 107 How this matrix is removed biochemically, or fails to form, is still unclear. Involvement of other proteases, perhaps the lysosomal family of cysteine protease cathepsins, may be important.108 112 The whole approach to the regulation of collagen deposition in renal tissue is ripe for new insight.
INFLAMMATORY CELLS
Tubulointerstitial fibrosis is typically conditioned by the infiltration of inflammatory cells113 including dendritic cells,114 lymphocytes,1,115,116 macrophages,117 and mast cells.118 Whereas inflammation as a whole contributes significantly to the engagement of fibrogenesis, evidence in recent years also highlights the antifibrotic effects of various subsets of lymphocytes and macrophages, providing novel potential avenues for antifibrotic therapies. Innate immunity through the activation of toll-like receptors 4 (TLR4)119 and TLR9,120 unlike TLR2 receptors,121 is an important early mediator of renal fibrogenesis. Lymphocytes precede the influx of macrophages.1 Rag-2 null mice, which lack both mature B and T lymphocytes, are protected from fibrosis, demonstrating that effector lymphocytes are an essential early component of fibrogenesis.116 Adoptive transfer of CD4 cells into Rag/ mice, but not CD8 cells so much, increases fibrogenesis.122 The contribution of CD3 T cells to renal fibrogenesis is well established, as activated cytotoxic T cells attack tubular epithelial cells.2 Administration of PGE1 inhibits the effector arm of T lymphocytes in interstitial nephritis that is overcome by competitive exposure to IL-1.123
1822
Long-term renal fibrosis after ischemiareperfusion injury also depends on persistent infiltration of effector-memory T lymphocytes, which correlate with onset of fibrosis in later stages.124 Transfer of T lymphocytes from mice with prolonged ischemia-reperfusion injury to nave recipients is sufficient to induce renal injury, further highlighting the relevance of memory lymphocytes in the progression of tubulointerstitial fibrosis.125 In contrast, FoxP3 regulatory T cells (Tregs) blunt kidney injury and are required for physiologic kidney regeneration.126 Whereas recent studies suggest the presence of CD20 B cells are as common as CD3 T lymphocytes in established fibrosis, the functional contribution of B cells to renal fibrogenesis is uncertain.2,127,128 When monocytes are recruited to damage the interstitium, they transdifferentiate into macrophages.129 There is a strong correlation between macrophage infiltration and the extent of fibrosis.130 Activation of TRL9 on macrophages by CpG-oligodeoxynucleotides is an accelerant for interstitial fibrogenesis,120 suggesting the dispersion of nuclear fragments after local cell death may enhance inflammation. Depletion of macrophages also ameliorates fibrogenesis in mice, highlighting the traditional profibrotic view of macrophages.131,132 Macrophages however can be categorized into classically activated M1 macrophages or alternatively activated M2 macrophages. Unlike the M1 macrophages, M2 macrophages are anti-inflammatory and provide cues for tissue repair.129 Infusion of cells enriched for M2 macrophages ameliorates renal fibrosis in mice.133 Finally, in addition to macrophages, dendritic cells are critical to antigen processing in tubulointerstitial injury;114 their proteasomal processing of albumin, for example, creates new antigenic targets.134 The balance or relative presence of these subsets of cells in renal inflammation over time needs more study. Mast cells are well-established contributors to fibrosis in lung, liver, and pancreas where they release proinflammatory cytokines, including chemokines CCL2-5, TNF, and leukotrienes.118 Surprisingly, however, mast cell defi-
cient KitW-sh/KitW-sh mice display enhanced fibrosis in the kidney. 118,135 Such accelerated fibrosis associates with increased levels of TGF, suggesting that mast cells in kidney play a role in suppressing the fibrotic process.118 Several new biologic modifiers of the immune system reduce interstitial fibrosis. PPAR agonists reduce the number of macrophages by attenuating TGF expression,30 and three independent studies report the administration of a CCR1 antagonist, anti-TNF blocking antibodies, or an IL-1 receptor antagonist are sufficient to ameliorate renal fibrosis, even when treatment is initiated in advancing disease.136 138 These therapeutic studies corroborate the role of inflammation not only in the initiation but also in perpetuation of fibrogenesis.
FIBROBLASTS
Fibroblasts in the renal interstitium are considered the principal source of fibrillar matrix (collagen types I and III), and tubulointerstitial fibrosis inevitably associates with a robust accumulation of fibroblasts,5 displaying increased intrinsic proliferative activity139,140 or, in some fibroblasts, what is called an activated phenotype expressing -smooth muscle actin (SMA).70,141,142 Tissue fibroblasts exhibit phenotypic heterogeneity,143145 more likely based on origin,54,146,147 but this heterogeneity in tissue is also bimodal: those cells that are RhoA-dependent SMA148 and those that are not. One generic dilemma with SMA is that when used as a fibroblast marker in injury, it is not distinguishable from SMA mural cellsvascular smooth muscle cells or venular pericytes;149,150 nor does this marker detect the larger population of SMA fibroblasts.58,146,147,151,152 The view of myofibroblasts as principal mediators of renal fibrosis is also based on the suggestion that fibrosis associates with de novo accumulation of SMA cells.51,153,154 This notion, however, has to be tempered by observations that SMA fibroblasts do not move,155 renal fibrogenesis persists despite decreasing
J Am Soc Nephrol 21: 1819 1834, 2010
www.jasn.org
BRIEF REVIEW
numbers of SMA myofibroblasts,121 SMA fibroblasts contain and likely express interstitial collagens in vivo,61,152 and mice deficient of SMA develop more fibrosis and their fibroblasts produce more collagen type I than SMA fibroblasts.156 Unequivocal functional data to support the idea that nonmotile SMA myofibroblasts principally mediate fibrogenesis is lacking. The most durable fibroblast marker in the kidney is fibroblast-specific protein-1 (FSP1; S100A4).58,146,147,151 The proclivity for FSP1 in fibroblasts, a member of the S100 family of calcium-binding proteins, was discovered in a differential genetic screen between fibroblasts and epithelial cells,157 and renal fibrosis associates with a robust accumulation of FSP1 fibroblasts.5,61,157 A few studies suggest FSP1 is expressed by macrophages;55,158,159 however, this notion persists from studies using underdetection methods for FSP1/S100A4 that may enhance nonspecific staining and/or from improper application of so-called antimacrophage antibodies that share target specificities with fibroblasts and are not macrophage-specific;158 160 FSP1 promoter activity in fibroblasts driving a GFP reporter60,161 or Cre recombinase162 clearly discriminate tissue fibroblasts from F4/80 macrophages. FSP1, F4/80 fibroblasts are also the only population in the kidney proven to contribute to fibrogenesis, as their ablation in FSP1-tk transgenic mice ameliorates fibrosis substantially.61 This kind of functional deletion experiment is critical evidence not yet reported in FSP1 cells expressing SMA, particularly pericytes.54 For the moment, it is best to think of all tissue fibroblasts as potentially fibrogenic.58,147,152 The true heterogeneity of fibroblasts in the kidney may be understood by examining the different cellular origins of these cells.147 Pools of fibrogenic fibroblasts comingle either by proliferation of resident fibroblasts,163 some of which may be subject to local or time-dependent epigenetic effects;68,164 from local tubular epithelial cells51,59,157,165 or endothelial cells (simple squamous epithelia)51,166 after EMT or EndMT during tissue injury; after recruitment of FSP1,
J Am Soc Nephrol 21: 1819 1834, 2010
CD34 bone marrow derived fibrocytes;59,146 and perhaps from blood vessel shedding of SMA pericytes54,150 that derive developmentally from mesothelium through EMT.167,168 It is not yet clear whether FSP1, SMA pericytes54,55 should be considered true fibroblasts or a separate and unique phenotype of collagen-producing cells.150 As opposed to tissue-derived fibroblasts, CD34 bone marrow derived fibrocytes59 may also have a unique lineage from CD11b, CD115, Gr1 leukocyte progenitors under the control of CD4 T cells;56 some studies suggest these circulating fibrocytes do not contribute to tissue fibrogenesis,53,55 whereas other experiments suggest they can to a limited extent.50,56,59 For the moment, it is probably best to view multiple lineages as contributing to the final mix of fibroblast populations in tissue. It is entirely unknown if these various lineages have priority among individuals or different diseases or if there is individual variation or preference as fibrogenesis progresses. Depletion of interstitial fibroblasts by selectively corrupting their DNA replication is one classic strategy for experimental antifibrotic therapy.61 Conditional expression of an IB dominant-negative transgene in fibroblasts also attenuates fibrogenesis by inhibiting NF-B.60 But because specific targeting of fibroblasts has not yet been achieved without genetic manipulation, current antifibrotic therapies center on various other approaches; these approaches include blocking PDGF-C, 169 PDGFD,170 or TGF171,172 with neutralizing antibodies or using pirfenidone,173175 pyridoxamine, 176 ALK5 receptor kinase inhibitors,177 paricalcitol,178 Ras inhibitors,68,179 or PPAR agonists.30 Blockade of AT1R by the small molecule inhibitor CGP-48933 also attenuates interstitial fibrosis,180 as does inhibition of angiotensin II73 or aldosterone action.32,33
TUBULAR EPITHELIUM
Tubular epithelial cells spark the progression of fibrogenesis to their own
detriment. They do this by modulating their proliferation,23,181 or by providing proinflammatory chemokines and cytokines that induce mononuclear inflammation and the formation of fibroblasts (Figure 3).59,182184 These local cytokines provide critical signals mediating primary interstitial injury.185 Secondary interstitial damage after glomerulonephritis also depends on the tubular toxicity of glomerular proteinuria,1,186 the filtration of protein-bound cytokines from plasma to the tubular microenvironment,184,187 or possible cytokine leakage through bulk fluid flow from the afferent arteriole directly into the interstitial spaces associated with the juxtaglomerular apparatus.188 Hydrodynamic forces along the tubules themselves are also profibrotic.189 Tubular stretch from obstruction induces TGF and NF-B; increases in single nephron GFR and compensatory increases in fluid shear stress also decrease tPA and increase TGF. The epicenter for early molecular action by tubular epithelial cells is through NFB.190 Tubular cells toggle on NF-B after exposure to proteins from tubular fluid,134,191 activation of CD36 scavenger receptors,25 or exposure to connective tissue growth factor,192 CD40 ligand,193 angiotensin II,194,195 or aldosterone.32,33 Activation of NF-B is critical for initiating the downstream release of PAI-1 or chemokines and growth factors,196 particularly IL-1,137 IL-6,197 MCP-1/CCL2,198,199 RANTES/CCL5,113,200 or TNF.200 In opposition, administration of Smad7,201,202 paricalcitol,203 truncated IB,204 HGF,200,205 spironolactone,32,206 and decoy NF-B oligodeoxynucleotides207 all attenuate tubulointerstitial injury by inhibiting the activity of NF-B. Experimental inhibition of proinflammatory chemokines such as TNF or CCR1 has also been successful in preventing progressive interstitial injury.113,138 With time, persistent tubulointerstitial injury inevitably associates with mitochondrial dysfunction or loss,26,208 formation of aglomerular tubuli,209 tubular atrophy,27 and rampant interstitial fibrosis,146 creating the classic pathologic picture of renal progression.210 Major epithelial mechanisms contributing to
1823
BRIEF REVIEW
www.jasn.org
Figure 3. The cytokine milieu in fibrogenesis. NF-B activators and inhibitors compete for the engagement of mammalian target of rapamycin and release of chemokines and proinflammatory cytokines that draw macrophages, dendritic cells, and T lymphocytes to the tubulointerstitium. These mononuclear cells injure the tubular epithelia and activate fibroblasts. The transcriptional activation of EMT and EndMT is engaged by hypoxia and various cytokines, particularly TGF, EGF, and ILK. EMT inhibitors block the development of fibroblasts that deposit extracellular matrix into the fibrogenic interstitium.
chronic tubulointerstitial fibrosis are G2/M cell cycle arrest,181 cellular apoptosis, 211 and EMT-forming fibroblasts; 147,151 all three processes are modulated by the transcriptional repressor GLIS2.212 EMT is a fundamental process to create cells that will move,155 a modification in lineage maturation that disturbs the state of nuclear diapause in epithelial and endothelial cells.59,213 Although not all agree,54,159,214,215 11 studies confirm these transitions to fibroblasts in a variety of lineage-tracing experiments from different tissues, including kidney,50,59,60,165 intestine,216 liver,217 heart,166 lung,218 220 and endothelium50,166,221 using 10 different cell fate reporter constructs. The role of EMT in forming renal fibroblasts has been recently reviewed49 and debated;160 several of the lineagetracing studies unable to detect EMT or FSP1 fibroblasts are likely confounded by use of nonpreferred anti-FSP1/S100A4 antibodies and/or inadequate antigen-retrieval methods during tissue preparation,54,159,215 by relying on a collagen promoter driving green fluorescent protein used to detect fibroblasts that perhaps may not express in all fibroblasts because of methylation or enhancer bias,160 and by overlooking lineage evidence that SMA mural cells/peri1824
cytes may have emerged previously from EMT.167,168,222 It is increasingly clear that fibroblasts derive from multiple parental lineages, including epithelial cells, endothelial cells, and bone marrow endosteal cells. The status of pericytes in fibrogenesis remains an area of great interest that will require more functional evidence of their role one way or the other. Finally, although EMT is difficult to assess in humans who are not biopsied until there is clinical evidence of disease,5 early renal allograft biopsies suggest changes in epithelial phenotype supportive of transitions preceding fibrosis,223225 although not all agree.226 Glis2 mutations producing autosomal recessive NPHP7, a rare form of nephronophthisis, may be the first suggestive evidence of spontaneous or derepressed EMT causing renal fibrosis in humans.212,227 EMT induces a variety of intermediate cell phenotypes, not all of which complete their transition to fibroblasts.147,225 This intermediacy and its reversibility may depend on the variable persistence of endogenous perturbagens: hypoxia,165,228 230 TGF,231 EGF,231,232 PTHRP,233 and plasmin97 all induce EMT, as does activation of ILK49 or RAGE.234 Vitamin D receptors downregulate the re-
nin-angiotensin system driving EMT and TGF and receptor absence accelerates fibrogenesis.235 After induction, a hierarchy of transcription factors program EMT, including GLIS2212 and CBF-A,236 a master regulator of Snail,237 Twist,238 HMGA2, LEF-1, and Ets-1.236 Overexpression of Snail1237 induces EMT and fibrosis and recessive mutations in Glis2 spontaneously invoke EMT in tubular cells in mice with renal fibrosis;212 short interfering RNA knockdown of Snail1 also blocks EMT during vascular mural cell differentiation.222 There appears to be a gradualness to EMT events in the kidney,225 as indicated by the variably active signaling of -catenin, Snail, or Twist in watershed epithelial cells along chronically injured tubules that is based on the time-dependent permissiveness of local cytokine action. Whereas activation of the EMT program is a means for parental cells to resist proapoptotic stimuli,211,239 such tenuous protection from cell death also results in loss of parental cell phenotype.59,240 The true frequency of tubular epithelial cells that complete EMT and become fibroblasts is unknown, but likely depends on the persistence of inflammation, epigenetic control of fibrotic gene regulation,67 and ultimately the emergence of tubular atrophy with acellular scars that are the consequence of profibrotic cytokine exhaustion and tubular cell disappearance. The relevance of EMT for progression of renal fibrosis is highlighted by studies in which administration of bone morphogenic protein-7 (BMP7),80 HGF,241,242 the smallmolecule inhibitor ILK, QLT-0267,243 or Y-27632,aninhibitorofRho/ROCK244 allinhibit tubular EMT and ameliorate fibrogenesis. Trps1 operates downstream of BMP7 in the kidney,245 and the availability of Smad7 controlling the phosphorylation of Smad3 is normally assured by Trps1 inhibition of ubiquintination through Arkadia;246 Trps1 haploinsufficiency raises the levels of Arkadia,decreasingtheavailabilityofSmad7, and thus facilitating fibrosis through TGF/ Smad3mediated EMT. Induction of heat shock protein-72 (HSP72) also protects tubular epithelia from apoptosis, EMT, and fibrosis,239 and overexpression of klotho247 or
J Am Soc Nephrol 21: 1819 1834, 2010
www.jasn.org
BRIEF REVIEW
inhibition of the mammalian target of rapamycin248 attenuates fibrogenesis in a variety of experimental models. A pivotal determinant in the failure to recoverfrominterstitialinjuryistherelativeabsence of nephron regeneration in kidneys that become fibrotic.181 One reason for this is that glomerulotubular disconnections limit repair of nephrons.107,209 The glomerulotubular neck at the antivascular pole of the glomerular tuft is an at-risk break point for the formation of aglomerular tubuli249 and surprisingly angiotensin inhibition protects these unwanted separations.250 Another reason is that cell cycle arrest of tubular epithelium during acute kidney injury may stimulate profibrotic signaling.181 Whereas tubular cells along atrophic tubules variably increase their proliferative activity in advanced tubulointerstitial disease,210 this restorative potential may decline with aging through the modulation of the adipokine, zinc-2glycoprotein, known as Zag.23 The regenerative capacity of injured tubules absent persistent inflammation is likely the result of self-renewing tubular cells or perhaps progenitor cells within other niches along the nephron.31 A CD24, CD133 progenitor cell niche has been identified in the parietal epithelium of Bowmans capsule near the vascular pole,21,22,251 and the adoptive transfer of these cells at the time of tubular injury obviates the appearance of interstitial fibrosis.252 The glomerulotubular neck region is also where ex vivo differentiated embryonic stem cells traffic after adoptive transfer during development253 and may be a tubular niche not unlike the vascular pole.21 Expansion of renal progenitor cells is under the control of histone deacetylases and their enzymatic inhibition may offer restorative potential to the kidney.254
THE MICROVASCULATURE
pro- and antiangiogenic stimuli257,258 or loss of peritubular endothelial cells by EndMT-forming fibroblasts.50,259 The fibrotic tubulointerstitium is a hypoxic environment.260,261 Hypoxia results from microvascular rarefaction made worse by matrix expansion throughout the interstitium,258 requiring the oxygen gradient to diffuse greater distances from vasoconstricted or attenuated microvessels to adjacent ischemic tubules.230,260 Hypoxia also contributes directly to the progression of tubulointerstitial fibrosis by simulating EMT and promoting matrix accumulation from new fibroblasts.165 Different strategies to improve this chronic hypoxia during renal progression show some promise in experimental models of renal fibrosis. Angiotensin II inhibition increases capillary blood flow and cortical oxygen levels in normal renal tissues,262 and long-acting calcium channel blockers attenuates the hypoxia of angiotensin IIinduced tubulointerstitial injury.263 Inhibition of the vasoconstrictor, endothelin, is also renoprotective,264 particularly in combination with ACE inhibition.265 Activation of the hypoxia-inducible factor (HIF) pathway or stabilization of HIF proteins attenuates renal fibrosis as well.230,261,266 The ultimate goal of reversing microvascular rarefaction, however, has been difficult to achieve. Whereas the HIF pathway is an important inducer of angiogenic vascular endothelial growth factor (VEGF) proteins,230 systemic administration of VEGF121 does not improve renal microvascular disease.267 Whereas administration of the antifibrotic molecule, BMP7, blocks EMT in the kidney,80 its affect on EndMT in the kidney is unknown; however, BMP7 does inhibit EndMT, endothelial loss, and fibrogenesis in experimental cardiac fibrosis.166
Rarefaction of the peritubular vasculature with ensuing chronic hypoxia are hallmarks of tubulointerstitial fibrosis.107 In early stages of injury the peritubular vasculature is damaged by proapoptotic stimuli, particularly transient ischemia.255,256Progressive fibrosis then remodels the peritubular endothelial network governed by imbalance among
J Am Soc Nephrol 21: 1819 1834, 2010
GENETIC PREDISPOSITION TO RENAL PROGRESSION
kidney disease are rapidly emerging from epidemiologic studies, including age,268,269 nephron mass,7,270 gender,268,271 levels of calcidiol,272 sympathetic activity,273 obesity and diabetes,274 cardiovascular disease,275 genetic loci276 and polymorphisms,273,277279 and epigenetic modifications.19 But how these risk factors modulate fibrogenesis is still uncertain. Genetic polymorphisms in cytokine risk profiles in some instances can be explained using existing knowledge of fibrotic signaling pathways.278 In other cases, it is unclear why genetic polymorphisms in uromodulin280,281 or methenyltetrahydrofolate synthetase282 increase susceptibility to fibrogenesis. Insights into the role of epigenetics in renal progression and fibrogenesis are also just starting to emerge. For example, aberrant hypermethylation of selected genes including RASAL1, a suppressor of Ras signaling, contributes to perpetual fibroblast activation and fibrogenesis.68 Furthermore, there are large families of small, naturally occurring, noncoding RNAs that interfere post-transcriptionally with the stability or translation of coding mRNA;283 three prototypical families of interfering RNAs include short interfering RNAs (siRNA), microRNAs (miRNAs), and piwi-interacting RNAs (piRNA).284 miRNA-192, for example, promotes the activation of TGF/Smad3-mediated fibrosis in ureteral obstruction and 5/6 nephrectomy, 285 and in diabetic glomeruli, TGF stimulates miRNA-192 to synergize with deltaEF1 short hairpin RNAs that increase Col1a2 E-box activity in mesangial cells.286 Oddly enough, low levels of miRNA-192 in human kidney biopsies of diabetic nephropathy correlate with late presentation and less fibrosis. 164 Thus, the interfering RNA story becomes complicated quickly, largely because the network effect of multiple families is not addressed by studying the action of a single family member.
Whereas revelations regarding new cellular mechanismsofrenalfibrogenesiscontinueto flourish, the identification of key risk factors underlying the true biologic fate of renal tissue is far from clear. Risk factors for chronic
CONCLUSIONS
Major progress has been made during the last 20 years in characterizing the cel1825
BRIEF REVIEW
www.jasn.org
lular and molecular mechanisms of interstitial injury. The molecular events determining choice between self-limited repair of the tubulointerstitium or progressive fibrogenesis suggest that persistent cytokine pressure and the accumulation of unwanted inflammatory cells are the principal effectors of chronicity. There remains a gap in understanding the genetic drivers of this cytokine pressure or sensitivity, and our knowledge of how genetic polymorphisms and epigenetic modifications facilitate fibrogenesis are in their infancy. Modulating the pivotal role of tubular epithelial cells in their provision of profibrotic stimuli, and the difficulty in preventing microvascular rarefaction, remain new challenges for the future. The role of determining cells, particularly myofibroblasts or pericytes, in renal fibrogenesis needs more clarification in comparison to the known functionality of FSP1 fibroblasts. A deeper understanding of the molecular basis for fibroblast expansion and collagen accumulation also requires more work. New therapies to abrogate EMT are on the horizon but the chromatin biology modulating these phenotypic changes are unclear; determining the point of no return for intermediate states of transition is still an open question. Today, the distinction between profibrotic and antifibrotic stimuli also seems increasingly muddledsome macrophage, T cell subpopulations, and mast cells, many of which were once viewed as unequivocally pernicious, now seem renoprotective. Tissue proteases, also once considered renoprotective, in many respects now look as if they encourage fibrogenesis. The role of progenitor cells in regeneration and the depletion of stem cell niches along the adult nephron is also an underdeveloped area of investigation. Most importantly, although the presence of tubulointerstitial fibrosis has always implied an unalterable fate, this perception is changing in new preclinical studies using unique biologic modifiers. We have renewed optimism that in the not too distant future some of these novel insights will become clinically rel1826
evant for patients with chronic kidney disease.
ACKNOWLEDGMENTS
Some of the cited work came from NIH grants DK-46282 (E.G.N.) and DK-81576, DK-81687, and DK-74558 (M.Z.). We thank Youhua Liu, Raymond Harris, Robert Colvin, and Yash Kanwar for helpful comments regarding earlier drafts of this manuscript, and we apologize for the lack of space to cite many other interesting findings.
DISCLOSURES
None.
REFERENCES
1. Kuncio GS, Neilson EG, Haverty T: Mechanisms of tubulointerstitial fibrosis. Kidney Int 39: 550 556, 1991 2. Harris RC, Neilson EG: Toward a unified theory of renal progression. Annu Rev Med 57: 365380, 2006 3. Schainuck LI, Striker GE, Cutler RE, Benditt EP: Structural-functional correlations in renal disease. II. The correlations. Hum Pathol 1: 631 641, 1970 4. Bohle A, Bader R, Grund KE, Mackensen S, Neunhoeffer: Serum creatinine concentration and renal interstitial volume. Analysis of correlations in endocapillary (acute) glomerulonephritis and in moderately severe mesangioproliferative glomerulonephritis. Virchows Arch A Pathol Anat Histol 375: 8796, 1977 5. Nishitani Y, Iwano M, Yamaguchi Y, Harada K, Nakatani K, Akai Y, Nishino T, Shiiki H, Kanauchi M, Saito Y, Neilson EG: Fibroblast-specific protein 1 is a specific prognostic marker for renal survival in patients with IgAN. Kidney Int 68: 1078 1085, 2005 6. Bohle A, Christ H, Grund KE, Mackensen S: The role of the interstitium of the renal cortex in renal disease. Contrib Nephrol 16: 109 114, 1979 7. Luyckx VA, Brenner BM: The clinical importance of nephron mass. J Am Soc Nephrol 21: 898 910, 2010 8. Fliser D, Franek E, Joest M, Block S, Mutschler E, Ritz E: Renal function in the elderly: Impact of hypertension and cardiac function. Kidney Int 51: 1196 1204, 1997 9. Glassock RJ, Winearls C: Ageing and the glomerular filtration rate: Truths and consequences. Trans Am Clin Climatol Assoc 120: 419 428, 2009
10. Davies DF, Shock NW: Age changes in glomerular filtration rate, effective renal plasma flow, and tubular excretory capacity in adult males. J Clin Invest 29: 496 507, 1950 11. Abrass CK, Adcox MJ, Raugi GJ: Agingassociated changes in renal extracellular matrix. Am J Pathol 146: 742752, 1995 12. Baylis C, Corman B: The aging kidney: Insights from experimental studies. J Am Soc Nephrol 9: 699 709, 1998 13. Zhou XJ, Rakheja D, Yu X, Saxena R, Vaziri ND, Silva FG: The aging kidney. Kidney Int 74: 710 720, 2008 14. Rule AD, Am H, Cornell LD, Taler SJ, Cosio FG, Kremers WK, Textor SC, Stegall MD: The association between age and nephrosclerosis on renal biopsy among healthy adults. Ann Intern Med 152: 561567, 2010 15. Anderson S, Halter JB, Hazzard WR, Himmelfarb J, Horne FM, Kaysen GA, Kusek JW, Nayfield SG, Schmader K, Tian Y, Ashworth JR, Clayton CP, Parker RP, Tarver ED, Woolard NF, High KP: Prediction, progression, and outcomes of chronic kidney disease in older adults. J Am Soc Nephrol 20: 1199 1209, 2009 16. Yang H, Fogo AB: Cell senescence in the aging kidney. J Am Soc Nephrol 21: 1436 1439, 2010 17. Melk A, Ramassar V, Helms LM, Moore R, Rayner D, Solez K, Halloran PF: Telomere shortening in kidneys with age. J Am Soc Nephrol 11: 444 453, 2000 18. Wills LP, Schnellmann RG: Telomere shortening and regenerative capacity after acute kidney injury. J Am Soc Nephrol 21: 202204, 2010 19. Dressler GR: Epigenetics, development, and the kidney. J Am Soc Nephrol 19: 2060 2067, 2008 20. Gupta S, Verfaillie C, Chmielewski D, Kren S, Eidman K, Connaire J, Heremans Y, Lund T, Blackstad M, Jiang Y, Luttun A, Rosenberg ME: Isolation and characterization of kidney-derived stem cells. J Am Soc Nephrol 17: 3028 3040, 2006 21. Lasagni L, Romagnani P: Glomerular epithelial stem cells: The good, the bad, and the ugly. J Am Soc Nephrol 2010, in press 22. Romagnani P, Kalluri R: Possible mechanisms of kidney repair. Fibrogenesis Tissue Repair 2: 3, 2009 23. Schmitt R, Marlier A, Cantley LG: Zag expression during aging suppresses proliferation after kidney injury. J Am Soc Nephrol 19: 23752383, 2008 24. Ix JH, Sharma K: Mechanisms linking obesity, chronic kidney disease, and fatty liver disease: The roles of fetuin-A, adiponectin, and AMPK. J Am Soc Nephrol 21: 406 412, 2010 25. Okamura DM, Pennathur S, Pasichnyk K, Lopez-Guisa JM, Collins S, Febbraio M, Heinecke J, Eddy AA: CD36 regulates oxidative stress and inflammation in hyper-
J Am Soc Nephrol 21: 1819 1834, 2010
www.jasn.org
BRIEF REVIEW
26.
27.
28.
29.
30.
31.
32.
33.
34.
35.
36.
37.
cholesterolemic CKD. J Am Soc Nephrol 20: 495505, 2009 Coughlan MT, Thorburn DR, Penfold SA, Laskowski A, Harcourt BE, Sourris KC, Tan AL, Fukami K, Thallas-Bonke V, Nawroth PP, Brownlee M, Bierhaus A, Cooper ME, Forbes JM: RAGE-induced cytosolic ROS promote mitochondrial superoxide generation in diabetes. J Am Soc Nephrol 20: 742752, 2009 Moller JC, Skriver E, Olsen S, Maunsbach AB: Ultrastructural analysis of human proximal tubules and cortical interstitium in chronic renal disease. Virchows Arch A Pathol Anat Histopathol 402: 209237, 1984 Thomas SE, Anderson S, Gordon KL, Oyama TT, Shankland SJ, Johnson RJ: Tubulointerstitial disease in aging: Evidence for underlying peritubular capillary damage, a potential role for renal ischemia. J Am Soc Nephrol 9: 231242, 1998 Yang HC, Deleuze S, Zuo Y, Potthoff SA, Ma LJ, Fogo AB: The PPARgamma agonist pioglitazone ameliorates agingrelated progressive renal injury. J Am Soc Nephrol 20: 2380 2388, 2009 Kawai T, Masaki T, Doi S, Arakawa T, Yokoyama Y, Doi T, Kohno N, Yorioka N: PPAR-gamma agonist attenuates renal interstitial fibrosis and inflammation through reduction of TGF-beta. Lab Invest 89: 47 58, 2009 Humphreys BD, Valerius MT, Kobayashi A, Mugford JW, Soeung S, Duffield JS, McMahon AP, Bonventre JV: Intrinsic epithelial cells repair the kidney after injury. Cell Stem Cell 2: 284 291, 2008 Remuzzi G, Cattaneo D, Perico N: The aggravating mechanisms of aldosterone on kidney fibrosis. J Am Soc Nephrol 19: 1459 1462, 2008 Leroy V, De Seigneux S, Agassiz V, Hasler U, Rafestin-Oblin ME, Vinciguerra M, Martin PY, Feraille E: Aldosterone activates NFkappaB in the collecting duct. J Am Soc Nephrol 20: 131144, 2009 Tu X, Chen X, Xie Y, Shi S, Wang J, Chen Y, Li J: Anti-inflammatory renoprotective effect of clopidogrel and irbesartan in chronic renal injury. J Am Soc Nephrol 19: 77 83, 2008 Eddy AA: Molecular insights into renal interstitial fibrosis. J Am Soc Nephrol 7: 24952508, 1996 Haverty TP, Kelly CJ, Hines WH, Amenta PS, Watanabe M, Harper RA, Kefalides NA, Neilson EG: Characterization of a renal tubular epithelial cell line which secretes the autologous target antigen of autoimmune experimental interstitial nephritis. J Cell Biol 107: 1359 1368, 1988 Howard BV, Macarak EJ, Gunson D, Kefalides NA: Characterization of the collagen synthesized by endothelial cells in culture. Proc Natl Acad Sci U S A 73: 2361 2364, 1976
38. Eismann U, Sommer M, Kosmehl H, Appenroth D, Fleck C, Stein G: Fibronectin splice variantsprognostic markers for the stage of renal interstitial fibrosis in the rat. Nephron 92: 379 388, 2002 39. Hewitson TD, Darby IA, Bisucci T, Jones CL, Becker GJ:Evolution of tubulointerstitial fibrosis in experimental renal infection and scarring. J Am Soc Nephrol 9: 632642, 1998 40. Hewitson TD: Renal tubulointerstitial fibrosis: Common but never simple. Am J Physiol Renal Physiol 296: F1239 F1244, 2009 41. Chen CZ, Raghunath M: Focus on collagen: In vitro systems to study fibrogenesis and antifibrosis state of the art. Fibrogenesis Tissue Repair 2: 7, 2009 42. Dallas SL, Chen Q, Sivakumar P: Dynamics of assembly and reorganization of extracellular matrix proteins. Curr Top Dev Biol 75: 124, 2006 43. Kadler KE, Hill A, Canty-Laird EG: Collagen fibrillogenesis: Fibronectin, integrins, and minor collagens as organizers and nucleators. Curr Opin Cell Biol 20: 495501, 2008 44. Bradshaw AD: The role of SPARC in extracellular matrix assembly. J Cell Commun Signal 2009 45. Holmes DF, Kadler KE: The 104 microfibril structure of thin cartilage fibrils. Proc Natl Acad Sci U S A 103: 17249 17254, 2006 46. Bradshaw AD, Sage EH: SPARC, a matricellular protein that functions in cellular differentiation and tissue response to injury. J Clin Invest 107: 1049 1054, 2001 47. Tremble PM, Lane TF, Sage EH, Werb Z: SPARC, a secreted protein associated with morphogenesis and tissue remodeling, induces expression of metalloproteinases in fibroblasts through a novel extracellular matrix-dependent pathway. J Cell Biol 121: 14331444, 1993 48. Pichler RH, Hugo C, Shankland SJ, Reed MJ, Bassuk JA, Andoh TF, Lombardi DM, Schwartz SM, Bennett WM, Alpers CE, Sage EH, Johnson RJ, Couser WG: SPARC is expressed in renal interstitial fibrosis and in renal vascular injury. Kidney Int 50: 1978 1989, 1996 49. Liu Y: New insights into epithelial-mesenchymal transition in kidney fibrosis. J Am Soc Nephrol 21: 212222, 2010 50. Zeisberg EM, Potenta SE, Sugimoto H, Zeisberg M, Kalluri R: Fibroblasts in kidney fibrosis emerge via endothelial-to-mesenchymal transition. J Am Soc Nephrol 19: 22822287, 2008 51. Zeisberg M, Kalluri R: Fibroblasts emerge via epithelial-mesenchymal transition in chronic kidney fibrosis. Front Biosci 13: 6991 6998, 2008 52. Neilson EG, McCafferty E, Feldman A, Clayman MD, Zakheim B, Korngold R: Spontaneous interstitial nephritis in kdkd mice. I. An experimental model of autoim-
53.
54.
55.
56.
57.
58.
59.
60.
61.
62.
63.
64.
mune renal disease. J Immunol 133: 2560 2565, 1984 Roufosse C, Bou-Gharios G, Prodromidi E, Alexakis C, Jeffery R, Khan S, Otto WR, Alter J, Poulsom R, Cook HT: Bone marrow-derived cells do not contribute significantly to collagen I synthesis in a murine model of renal fibrosis. J Am Soc Nephrol 17: 775782, 2006 Humphreys BD, Lin SL, Kobayashi A, Hudson TE, Nowlin BT, Bonventre JV, Valerius MT, McMahon AP, Duffield JS: Fate tracing reveals the pericyte and not epithelial origin of myofibroblasts in kidney fibrosis. Am J Pathol 176: 8597, 2010 Lin SL, Kisseleva T, Brenner DA, Duffield JS: Pericytes and perivascular fibroblasts are the primary source of collagen-producing cells in obstructive fibrosis of the kidney. Am J Pathol 173: 16171627, 2008 Niedermeier M, Reich B, Rodriguez Gomez M, Denzel A, Schmidbauer K, Gobel N, Talke Y, Schweda F, Mack M: CD4 T cells control the differentiation of Gr1 monocytes into fibrocytes. Proc Natl Acad Sci U S A 106: 1789217897, 2009 Taguchi T, Razzaque MS: The collagen-specific molecular chaperone HSP47: Is there a role in fibrosis? Trends Mol Med 13: 4553, 2007 Okada H, Ban S, Nagao S, Takahashi H, Suzuki H, Neilson EG: Progressive renal fibrosis in murine polycystic kidney disease: An immunohistochemical observation. Kidney Int 58: 587597, 2000 Iwano M, Plieth D, Danoff TM, Xue C, Okada H, Neilson EG: Evidence that fibroblasts derive from epithelium during tissue fibrosis. J Clin Invest 110: 341350, 2002 Inoue T, Takenaka T, Hayashi M, Monkawa T, Yoshino J, Shimoda K, Neilson EG, Suzuki H, Okada H: Fibroblast expression of an IB-dominant negative transgene attenuates renal fibrosis. J Am Soc Nephrol 2010, in press Iwano M, Fischer A, Okada H, Plieth D, Xue C, Danoff TM, Neilson EG: Conditional abatement of tissue fibrosis using nucleoside analogs to selectively corrupt DNA replication in transgenic fibroblasts. Mol Ther 3: 149 159, 2001 McDougall S, Dallon J, Sherratt J, Maini P: Fibroblast migration and collagen deposition during dermal wound healing: Mathematical modelling and clinical implications. Philos Transact A Math Phys Eng Sci 364: 13851405, 2006 Whitby DJ, Ferguson MW: Immunohistochemical localization of growth factors in fetal wound healing. Dev Biol 147: 207 215, 1991 Schnaper HW, Jandeska S, Runyan CE, Hubchak SC, Basu RK, Curley JF, Smith RD, Hayashida T: TGF-beta signal transduction in chronic kidney disease. Front Biosci 14: 2448 2465, 2009
J Am Soc Nephrol 21: 1819 1834, 2010
1827
BRIEF REVIEW
www.jasn.org
65. Murphy M, Docherty NG, Griffin B, Howlin J, McArdle E, McMahon R, Schmid H, Kretzler M, Droguett A, Mezzano S, Brady HR, Furlong F, Godson C, Martin F: IHG-1 amplifies TGF-beta1 signaling and is increased in renal fibrosis. J Am Soc Nephrol 19: 16721680, 2008 66. Kato M, Arce L, Natarajan R: MicroRNAs and their role in progressive kidney diseases. Clin J Am Soc Nephrol 4: 1255 1266, 2009 67. Noh H, Oh EY, Seo JY, Yu MR, Kim YO, Ha H, Lee HB: Histone deacetylase-2 is a key regulator of diabetes- and transforming growth factor-beta1-induced renal injury. Am J Physiol Renal Physiol 297: F729 F739, 2009 68. Bechtel W, McGoohan S, Zeisberg EM, Muller GA, Kalbacher H, Salant DJ, Muller CA, Kalluri R, Zeisberg M: Methylation determines fibroblast activation and fibrogenesis in the kidney. Nat Med 16: 544 550, 2010 69. Rosenbloom J, Castro SV, Jimenez SA: Narrative review: Fibrotic diseases: Cellular and molecular mechanisms and novel therapies. Ann Intern Med 152: 159 166, 2010 70. Wynn TA: Cellular and molecular mechanisms of fibrosis. J Pathol 214: 199 210, 2008 71. Border WA, Noble NA: Interactions of transforming growth factor-beta and angiotensin II in renal fibrosis. Hypertension 31: 181188, 1998 72. Matsuo S, Lopez-Guisa JM, Cai X, Okamura DM, Alpers CE, Bumgarner RE, Peters MA, Zhang G, Eddy AA: Multifunctionality of PAI-1 in fibrogenesis: Evidence from obstructive nephropathy in PAI-1overexpressing mice. Kidney Int 67: 2221 2238, 2005 73. Ruster C, Wolf G: Renin-angiotensin-aldosterone system and progression of renal disease. J Am Soc Nephrol 17: 29852991, 2006 74. Border WA, Okuda S, Languino LR, Sporn MB, Ruoslahti E: Suppression of experimental glomerulonephritis by antiserum against transforming growth factor beta 1. Nature 346: 371374, 1990 75. Sharma K, Jin Y, Guo J, Ziyadeh FN: Neutralization of TGF-beta by anti-TGF-beta antibody attenuates kidney hypertrophy and the enhanced extracellular matrix gene expression in STZ-induced diabetic mice. Diabetes 45: 522530, 1996 76. Cosgrove D, Rodgers K, Meehan D, Miller C, Bovard K, Gilroy A, Gardner H, Kotelianski V, Gotwals P, Amatucci A, Kalluri R: Integrin alpha1beta1 and transforming growth factor-beta1 play distinct roles in alport glomerular pathogenesis and serve as dual targets for metabolic therapy. Am J Pathol 157: 1649 1659, 2000 77. Isaka Y, Brees DK, Ikegaya K, Kaneda Y, Imai E, Noble NA, Border WA: Gene ther-
78.
79.
80.
81.
82.
83.
84.
85.
86.
87.
88.
89.
90.
apy by skeletal muscle expression of decorin prevents fibrotic disease in rat kidney. Nat Med 2: 418 423, 1996 Ziyadeh FN, Hoffman BB, Han DC, Iglesias-De La Cruz MC, Hong SW, Isono M, Chen S, McGowan TA, Sharma K: Long-term prevention of renal insufficiency, excess matrix gene expression, and glomerular mesangial matrix expansion by treatment with monoclonal antitransforming growth factor-beta antibody in db/db diabetic mice. Proc Natl Acad Sci U S A 97: 80158020, 2000 Hugo C: The thrombospondin 1-TGF-beta axis in fibrotic renal disease. Nephrol Dial Transplant 18: 12411245, 2003 Zeisberg M, Hanai J, Sugimoto H, Mammoto T, Charytan D, Strutz F, Kalluri R: BMP-7 counteracts TGF-beta1-induced epithelial-to-mesenchymal transition and reverses chronic renal injury. Nat Med 9: 964 968, 2003 Gewin L, Bulus N, Mernaugh G, Moeckel G, Harris RC, Moses HL, Pozzi A, Zent R: TGF-{beta} receptor deletion in the renal collecting system exacerbates fibrosis. J Am Soc Nephrol 21: 1334 1343, 2010 Kopp JB: TGF signaling and the renal tubular epithelial cell: Too much, too little, and just right. J Am Soc Nephrol 21: 1241 1243, 2010 Mott JD, Werb Z: Regulation of matrix biology by matrix metalloproteinases. Curr Opin Cell Biol 16: 558 564, 2004 Cheng S, Lovett DH: Gelatinase A (MMP-2) is necessary and sufficient for renal tubular cell epithelial-mesenchymal transformation. Am J Pathol 162: 19371949, 2003 Sabeh F, Li XY, Saunders TL, Rowe RG, Weiss SJ: Secreted versus membrane-anchored collagenases: Relative roles in fibroblast-dependent collagenolysis and invasion. J Biol Chem 284: 2300123011, 2009 Catania JM, Chen G, Parrish AR: Role of matrix metalloproteinases in renal pathophysiologies. Am J Physiol Renal Physiol 292: F905F911, 2007 Ronco P, Chatziantoniou C: Matrix metalloproteinases and matrix receptors in progression and reversal of kidney disease: therapeutic perspectives. Kidney Int 74: 873 878, 2008 Zeisberg M, Khurana M, Rao VH, Cosgrove D, Rougier JP, Werner MC, Shield CF, Werb Z, Kalluri R: Stage-specific action of matrix metalloproteinases influences progressive hereditary kidney disease. PLoS Med 3: e100, 2006 Cheng S, Pollock AS, Mahimkar R, Olson JL, Lovett DH: Matrix metalloproteinase 2 and basement membrane integrity: A unifying mechanism for progressive renal injury. FASEB J 20: 1898 1900, 2006 Kassiri Z, Oudit GY, Kandalam V, Awad A, Wang X, Ziou X, Maeda N, Herzenberg AM, Scholey JW: Loss of TIMP3 enhances
91.
92.
93.
94.
95.
96.
97.
98.
99.
100.
101.
102.
103.
interstitial nephritis and fibrosis. J Am Soc Nephrol 20: 12231235, 2009 Ota I, Li XY, Hu Y, Weiss SJ: Induction of a MT1-MMP and MT2-MMP-dependent basement membrane transmigration program in cancer cells by Snail1. Proc Natl Acad Sci U S A 106: 20318 20323, 2009 Rowe RG, Li XY, Hu Y, Saunders TL, Virtanen I, Garcia de Herreros A, Becker KF, Ingvarsen S, Engelholm LH, Bommer GT, Fearon ER, Weiss SJ: Mesenchymal cells reactivate Snail1 expression to drive threedimensional invasion programs. J Cell Biol 184: 399 408, 2009 Eddy AA, Fogo AB: Plasminogen activator inhibitor-1 in chronic kidney disease: Evidence and mechanisms of action. J Am Soc Nephrol 17: 2999 3012, 2006 Eddy AA: Plasminogen activator inhibitor-1 and the kidney. Am J Physiol Renal Physiol 283: F209 F220, 2002 Birkedal-Hansen H, Taylor RE, Bhown AS, Katz J, Lin HY, Wells BR: Cleavage of bovine skin type III collagen by proteolytic enzymes. Relative resistance of the fibrillar form. J Biol Chem 260: 1641116417, 1985 Nagase H: Activation mechanisms of matrix metalloproteinases. Biol Chem 378: 151160, 1997 Zhang G, Kernan KA, Collins SJ, Cai X, Lopez-Guisa JM, Degen JL, Shvil Y, Eddy AA: Plasmin(ogen) promotes renal interstitial fibrosis by promoting epithelial-tomesenchymal transition: role of plasminactivated signals. J Am Soc Nephrol 18: 846 859, 2007 Yang J, Shultz RW, Mars WM, Wegner RE, Li Y, Dai C, Nejak K, Liu Y: Disruption of tissue-type plasminogen activator gene in mice reduces renal interstitial fibrosis in obstructive nephropathy. J Clin Invest 110: 15251538, 2002 Zhang G, Kim H, Cai X, Lopez-Guisa JM, Alpers CE, Liu Y, Carmeliet P, Eddy AA: Urokinase receptor deficiency accelerates renal fibrosis in obstructive nephropathy. J Am Soc Nephrol 14: 1254 1271, 2003 Fintha A, Sebe A, Masszi A, Terebessy T, Huszar T, Rosivall L, Mucsi I: Angiotensin II activates plasminogen activator inhibitor-I promoter in renal tubular epithelial cells via the AT1 receptor. Acta Physiol Hung 94: 19 30, 2007 Jung GS, Kim MK, Choe MS, Lee KM, Kim HS, Park YJ, Choi HS, Lee KU, Park KG, Lee IK: The orphan nuclear receptor SHP attenuates renal fibrosis. J Am Soc Nephrol 20: 21622170, 2009 Oda T, Jung YO, Kim HS, Cai X, LopezGuisa JM, Ikeda Y, Eddy AA: PAI-1 deficiency attenuates the fibrogenic response to ureteral obstruction. Kidney Int 60: 587 596, 2001 Krag S, Danielsen CC, Carmeliet P, Nyengaard J, Wogensen L: Plasminogen activa-
1828
J Am Soc Nephrol 21: 1819 1834, 2010
www.jasn.org
BRIEF REVIEW
104.
105.
106.
107.
108.
109.
110.
111.
112.
113.
114.
115.
tor inhibitor-1 gene deficiency attenuates TGF-beta1-induced kidney disease. Kidney Int 68: 26512666, 2005 Zeisberg M, Bottiglio C, Kumar N, Maeshima Y, Strutz F, Muller GA, Kalluri R: Bone morphogenic protein-7 inhibits progression of chronic renal fibrosis associated with two genetic mouse models. Am J Physiol Renal Physiol 285: F1060 F1067, 2003 Sugimoto H, Grahovac G, Zeisberg M, Kalluri R: Renal fibrosis and glomerulosclerosis in a new mouse model of diabetic nephropathy and its regression by bone morphogenic protein-7 and advanced glycation end product inhibitors. Diabetes 56: 18251833, 2007 Adamczak M, Gross ML, Krtil J, Koch A, Tyralla K, Amann K, Ritz E: Reversal of glomerulosclerosis after high-dose enalapril treatment in subtotally nephrectomized rats. J Am Soc Nephrol 14: 28332842, 2003 Thornhill BA, Forbes MS, Marcinko ES, Chevalier RL: Glomerulotubular disconnection in neonatal mice after relief of partial ureteral obstruction. Kidney Int 72: 1103 1112, 2007 Everts V, van der Zee E, Creemers L, Beertsen W: Phagocytosis and intracellular digestion of collagen, its role in turnover and remodelling. Histochem J 28: 229 245, 1996 Hilliard LM, Russo LM, Comper WD: Hypertension-mediated albuminuria is associated with reduced lysosomal activity in the kidney and the heart. Am J Nephrol 29: 454 464, 2009 Shimoda N, Fukazawa N, Nonomura K, Fairchild RL: Cathepsin g is required for sustained inflammation and tissue injury after reperfusion of ischemic kidneys. Am J Pathol 170: 930 940, 2007 Sebekova K, Paczek L, Dammrich J, Ling H, Spustova V, Gaciong Z, Heidland A: Effects of protease therapy in the remnant kidney model of progressive renal failure. Miner Electrolyte Metab 23: 291295, 1997 Huang S, Schaefer RM, Reisch S, Paczek L, Schaefer L, Teschner M, Sebekova K, Heidland A: Suppressed activities of cathepsins and metalloproteinases in the chronic model of puromycin aminonucleoside nephrosis. Kidney Blood Press Res 22: 121 127, 1999 Vielhauer V, Berning E, Eis V, Kretzler M, Segerer S, Strutz F, Horuk R, Grone HJ, Schlondorff D, Anders HJ: CCR1 blockade reduces interstitial inflammation and fibrosis in mice with glomerulosclerosis and nephrotic syndrome. Kidney Int 66: 2264 2278, 2004 John R, Nelson PJ: Dendritic cells in the kidney. J Am Soc Nephrol 18: 2628 2635, 2007 Kelly CJ: Cellular immunity and the tubu-
116.
117.
118.
119.
120.
121.
122.
123.
124.
125.
126.
127.
lointerstitium. Semin Nephrol 19: 182187, 1999 Lebleu VS, Sugimoto H, Miller CA, Gattone VH, 2nd, Kalluri R: Lymphocytes are dispensable for glomerulonephritis but required for renal interstitial fibrosis in matrix defect-induced Alport renal disease. Lab Invest 88: 284 292, 2008 Sean Eardley K, Cockwell P: Macrophages and progressive tubulointerstitial disease. Kidney Int 68: 437 455, 2005 Holdsworth SR, Summers SA: Role of mast cells in progressive renal diseases. J Am Soc Nephrol 19: 2254 2261, 2008 Pulskens WP, Rampanelli E, Teske GJ, Butter LM, Claessen N, Luirink IK, Poll TV, Florquin S, Leemans, JC: TLR4 promotes fibrosis but attenuates tubular damage in progressive renal injury. J Am Soc Nephrol 21: 1299 1308, 2010 Anders HJ, Vielhauer V, Eis V, Linde Y, Kretzler M, Perez de Lema G, Strutz F, Bauer S, Rutz M, Wagner H, Grone HJ, Schlondorff D: Activation of toll-like receptor-9 induces progression of renal disease in MRL-Fas(lpr) mice. FASEB J 18: 534 536, 2004 Leemans JC, Butter LM, Pulskens WP, Teske GJ, Claessen N, van der Poll T, Florquin S: The role of Toll-like receptor 2 in inflammation and fibrosis during progressive renal injury. PLoS One 4: e5704, 2009 Tapmeier TT, Fearn A, Brown K, Chowdhury P, Sacks SH, Sheerin NS, Wong W: Pivotal role of CD4() T cells in renal fibrosis following ureteric obstruction. Kidney Int 78: 351362, 2010 Kelly CJ, Zurier RB, Krakauer KA, Blanchard N, Neilson EG: Prostaglandin E1 inhibits effector T cell induction and tissue damage in experimental murine interstitial nephritis. J Clin Invest 79: 782789, 1987 Ascon M, Ascon DB, Liu M, Cheadle C, Sarkar C, Racusen L, Hassoun HT, Rabb H: Renal ischemia-reperfusion leads to long term infiltration of activated and effectormemory T lymphocytes. Kidney Int 75: 526 535, 2009 Burne-Taney MJ, Liu M, Ascon D, Molls RR, Racusen L, Rabb H: Transfer of lymphocytes from mice with renal ischemia can induce albuminuria in naive mice: A possible mechanism linking early injury and progressive renal disease? Am J Physiol Renal Physiol 291: F981F986, 2006 Gandolfo MT, Jang HR, Bagnasco SM, Ko GJ, Agreda P, Satpute SR, Crow MT, King LS, Rabb H: Foxp3 regulatory T cells participate in repair of ischemic acute kidney injury. Kidney Int 76: 717729, 2009 Heller F, Lindenmeyer MT, Cohen CD, Brandt U, Draganovici D, Fischereder M, Kretzler M, Anders HJ, Sitter T, Mosberger I, Kerjaschki D, Regele H, Schlondorff D, Segerer S: The contribution of B cells to
128.
129.
130.
131.
132.
133.
134.
135.
136.
137.
138.
139.
renal interstitial inflammation. Am J Pathol 170: 457 468, 2007 Segerer S, Schlondorff D: B cells and tertiary lymphoid organs in renal inflammation. Kidney Int 73: 533537, 2008 Ricardo SD, van Goor H, Eddy AA: Macrophage diversity in renal injury and repair. J Clin Invest 118: 35223530, 2008 Nishida M, Hamaoka K: Macrophage phenotype and renal fibrosis in obstructive nephropathy. Nephron Exp Nephrol 110: e31 e36, 2008 Ko GJ, Boo CS, Jo SK, Cho WY, Kim HK: Macrophages contribute to the development of renal fibrosis following ischaemia/ reperfusion-induced acute kidney injury. Nephrol Dial Transplant 23: 842 852, 2008 Duffield JS, Forbes SJ, Constandinou CM, Clay S, Partolina M, Vuthoori S, Wu S, Lang R, Iredale JP: Selective depletion of macrophages reveals distinct, opposing roles during liver injury and repair. J Clin Invest 115: 56 65, 2005 Wang Y, Wang YP, Zheng G, Lee VW, Ouyang L, Chang DH, Mahajan D, Coombs J, Wang YM, Alexander SI, Harris DC: Ex vivo programmed macrophages ameliorate experimental chronic inflammatory renal disease. Kidney Int 72: 290 299, 2007 Macconi D, Chiabrando C, Schiarea S, Aiello S, Cassis L, Gagliardini E, Noris M, Buelli S, Zoja C, Corna D, Mele C, Fanelli R, Remuzzi G, Benigni A: Proteasomal processing of albumin by renal dendritic cells generates antigenic peptides. J Am Soc Nephrol 20: 123130, 2009 Miyazawa S, Hotta O, Doi N, Natori Y, Nishikawa K, Natori Y: Role of mast cells in the development of renal fibrosis: Use of mast cell-deficient rats. Kidney Int 65: 2228 2237, 2004 Anders HJ, Belemezova E, Eis V, Segerer S, Vielhauer V, Perez de Lema G, Kretzler M, Cohen CD, Frink M, Horuk R, Hudkins KL, Alpers CE, Mampaso F, Schlondorff D: Late onset of treatment with a chemokine receptor CCR1 antagonist prevents progression of lupus nephritis in MRLFas(lpr) mice. J Am Soc Nephrol 15: 1504 1513, 2004 Jones LK, OSullivan KM, Semple T, Kuligowski MP, Fukami K, Ma FY, Nikolic-Paterson DJ, Holdsworth SR, Kitching AR: IL-1RI deficiency ameliorates early experimental renal interstitial fibrosis. Nephrol Dial Transplant 24: 3024 3032, 2009 Khan SB, Cook HT, Bhangal G, Smith J, Tam FW, Pusey CD: Antibody blockade of TNF-alpha reduces inflammation and scarring in experimental crescentic glomerulonephritis. Kidney Int 67: 18121820, 2005 Muller GA, Rodemann HP: Characterization of human renal fibroblasts in health and disease: I. Immunophenotyping of cultured tubular epithelial cells and fibroblasts derived from kidneys with histologically
J Am Soc Nephrol 21: 1819 1834, 2010
1829
BRIEF REVIEW
www.jasn.org
140.
141.
142.
143. 144.
145.
146.
147.
148.
149.
150.
151.
152.
153.
154.
155.
proven interstitial fibrosis. Am J Kidney Dis 17: 680 683, 1991 Rodemann HP, Muller GA: Characterization of human renal fibroblasts in health and disease: II. In vitro growth, differentiation, and collagen synthesis of fibroblasts from kidneys with interstitial fibrosis. Am J Kidney Dis 17: 684 686, 1991 Kaissling B, Le Hir M: The renal cortical interstitium: morphological and functional aspects. Histochem Cell Biol 130: 247262, 2008 Grande MT, Lopez-Novoa JM: Fibroblast activation and myofibroblast generation in obstructive nephropathy. Nat Rev Nephrol 5: 319 328, 2009 Kalluri R, Zeisberg M: Fibroblasts in cancer. Nat Rev Cancer 6: 392 401, 2006 Bayreuther K, Rodemann HP, Hommel R, Dittmann K, Albiez M, Francz PI: Human skin fibroblasts in vitro differentiate along a terminal cell lineage. Proc Natl Acad Sci U S A 85: 51125116, 1988 Schor SL, Schor AM: Clonal heterogeneity in fibroblast phenotype: Implications for the control of epithelial-mesenchymal interactions. Bioessays 7: 200 204, 1987 Kalluri R, Neilson EG: Epithelial-mesenchymal transition and its implications for fibrosis. J Clin Invest 112: 1776 1784, 2003 Zeisberg M, Neilson EG: Biomarkers for epithelial-mesenchymal transitions. J Clin Invest 119: 1429 1437, 2009 Hutchison N, Hendry BM, Sharpe CC: Rho isoforms have distinct and specific functions in the process of epithelial to mesenchymal transition in renal proximal tubular cells. Cell Signal 21: 15221531, 2009 Morikawa S, Baluk P, Kaidoh T, Haskell A, Jain RK, McDonald DM: Abnormalities in pericytes on blood vessels and endothelial sprouts in tumors. Am J Pathol 160: 985 1000, 2002 Diaz-Flores L, Gutierrez R, Madrid JF, Varela H, Valladares F, Acosta E, MartinVasallo P, Diaz-Flores, L Jr.: Pericytes. Morphofunction, interactions and pathology in a quiescent and activated mesenchymal cell niche. Histol Histopathol 24: 909 969, 2009 Neilson EG: Mechanisms of disease: Fibroblastsa new look at an old problem. Nat Clin Pract Nephrol 2: 101108, 2006 Okada H, Inoue T, Kanno Y, Kobayashi T, Ban S, Kalluri R, Suzuki H: Renal fibroblastlike cells in Goodpasture syndrome rats. Kidney Int 60: 597 606, 2001 Zeisberg M, Strutz F, Muller GA: Role of fibroblast activation in inducing interstitial fibrosis. J Nephrol 13 [Suppl 3]: S111 S120, 2000 Gabbiani G: The myofibroblast in wound healing and fibrocontractive diseases. J Pathol 200: 500 503, 2003 Hay ED: The mesenchymal cell, its role in the embryo, and the remarkable signaling
156.
157.
158.
159.
160.
161.
162.
163.
164.
165.
166.
167.
mechanisms that create it. Dev Dyn 233: 706 720, 2005 Takeji M, Moriyama T, Oseto S, Kawada N, Hori M, Imai E, Miwa T: Smooth muscle alpha-actin deficiency in myofibroblasts leads to enhanced renal tissue fibrosis. J Biol Chem 281: 40193 40200, 2006 Strutz F, Okada H, Lo CW, Danoff T, Carone RL, Tomaszewski JE, Neilson EG: Identification and characterization of a fibroblast marker: FSP1. J Cell Biol 130: 393 405, 1995 Le Hir M, Hegyi I, Cueni-Loffing D, Loffing J, Kaissling B: Characterization of renal interstitial fibroblast-specific protein 1/S100A4-positive cells in healthy and inflamed rodent kidneys. Histochem Cell Biol 123: 335346, 2005 Li L, Zepeda-Orozco D, Black R, Lin F: Autophagy is a component of epithelial cell fate in obstructive uropathy. Am J Pathol 176: 17671778, 2010 Zeisberg M, Duffield JS: Resolved: EMT produces fibroblasts in the kidney. J Am Soc Nephrol 21: 12471253, 2010 Inoue T, Plieth D, Venkov CD, Xu C, Neilson EG: Antibodies against macrophages that overlap in specificity with fibroblasts. Kidney Int 67: 2488 2493, 2005 Trimboli AJ, Cantemir-Stone CZ, Li F, Wallace JA, Merchant A, Creasap N, Thompson JC, Caserta E, Wang H, Chong JL, Naidu S, Wei G, Sharma SM, Stephens JA, Fernandez SA, Gurcan MN, Weinstein MB, Barsky SH, Yee L, Rosol TJ, Stromberg PC, Robinson ML, Pepin F, Hallett M, Park M, Ostrowski MC, Leone G: Pten in stromal fibroblasts suppresses mammary epithelial tumours. Nature 461: 1084 1091, 2009 Floege J, Eitner F, Alpers CE: A new look at platelet-derived growth factor in renal disease. J Am Soc Nephrol 19: 1223, 2008 Krupa A, Jenkins R, Luo DD, Lewis A, Phillips A, Fraser D: Loss of microRNA-192 promotes fibrogenesis in diabetic nephropathy. J Am Soc Nephrol 21: 438 447, 2010 Higgins DF, Kimura K, Bernhardt WM, Shrimanker N, Akai Y, Hohenstein B, Saito Y, Johnson RS, Kretzler M, Cohen CD, Eckardt KU, Iwano M, Haase VH: Hypoxia promotes fibrogenesis in vivo via HIF-1 stimulation of epithelial-tomesenchymal transition. J Clin Invest 117: 3810 3820, 2007 Zeisberg EM, Tarnavski O, Zeisberg M, Dorfman AL, McMullen JR, Gustafsson E, Chandraker A, Yuan X, Pu WT, Roberts AB, Neilson EG, Sayegh MH, Izumo S, Kalluri R: Endothelial-to-mesenchymal transition contributes to cardiac fibrosis. Nat Med 13: 952961, 2007 Wilm B, Ipenberg A, Hastie ND, Burch JB, Bader DM: The serosal mesothelium is a major source of smooth muscle cells of the gut vasculature. Development 132: 5317 5328, 2005
168. Que J, Wilm B, Hasegawa H, Wang F, Bader D, Hogan BL: Mesothelium contributes to vascular smooth muscle and mesenchyme during lung development. Proc Natl Acad Sci U S A 105: 16626 16630, 2008 169. Eitner F, Bucher E, van Roeyen C, Kunter U, Rong S, Seikrit C, Villa L, Boor P, Fredriksson L, Backstrom G, Eriksson U, Ostman A, Floege J, Ostendorf T: PDGF-C is a proinflammatory cytokine that mediates renal interstitial fibrosis. J Am Soc Nephrol 19: 281289, 2008 170. Boor P, Konieczny A, Villa L, Kunter U, van Roeyen CR, LaRochelle WJ, Smithson G, Arrol S, Ostendorf T, Floege J: PDGF-D inhibition by CR002 ameliorates tubulointerstitial fibrosis following experimental glomerulonephritis. Nephrol Dial Transplant 22: 13231331, 2007 171. Xin J, Homma T, Matsusaka T, Ma J, Isaka Y, Imai E, Ichikawa I: Suppression of cyclosporine a nephrotoxicity in vivo by transforming growth factor beta receptor-immunoglobulin G chimeric protein. Transplantation 77: 14331442, 2004 172. Benigni A, Zoja C, Corna D, Zatelli C, Conti S, Campana M, Gagliardini E, Rottoli D, Zanchi C, Abbate M, Ledbetter S, Remuzzi G: Add-on anti-TGF-beta antibody to ACE inhibitor arrests progressive diabetic nephropathy in the rat. J Am Soc Nephrol 14: 1816 1824, 2003 173. Miric G, Dallemagne C, Endre Z, Margolin S, Taylor SM, Brown L: Reversal of cardiac and renal fibrosis by pirfenidone and spironolactone in streptozotocin-diabetic rats. Br J Pharmacol 133: 687 694, 2001 174. RamachandraRao SP, Zhu Y, Ravasi T, McGowan TA, Toh I, Dunn SR, Okada S, Shaw MA, Sharma K: Pirfenidone is renoprotective in diabetic kidney disease. J Am Soc Nephrol 20: 17651775, 2009 175. Shimizu T, Fukagawa M, Kuroda T, Hata S, Iwasaki Y, Nemoto M, Shirai K, Yamauchi S, Margolin SB, Shimizu F, Kurokawa K: Pirfenidone prevents collagen accumulation in the remnant kidney in rats with partial nephrectomy. Kidney Int Suppl 63: S239S243, 1997 176. Waanders F, van den Berg E, Nagai R, van Veen I, Navis G, van Goor H: Renoprotective effects of the AGE-inhibitor pyridoxamine in experimental chronic allograft nephropathy in rats. Nephrol Dial Transplant 23: 518 524, 2008 177. Moon JA, Kim HT, Cho IS, Sheen YY, Kim DK: IN-1130, a novel transforming growth factor-beta type I receptor kinase (ALK5) inhibitor, suppresses renal fibrosis in obstructive nephropathy. Kidney Int 70: 1234 1243, 2006 178. Tan X, Li Y, Liu Y: Paricalcitol attenuates renal interstitial fibrosis in obstructive nephropathy. J Am Soc Nephrol 17: 3382 3393, 2006 179. Sharpe CC, Dockrell ME, Scott R, Noor MI,
1830
J Am Soc Nephrol 21: 1819 1834, 2010
www.jasn.org
BRIEF REVIEW
180.
181.
182.
183.
184.
185.
186.
187.
188.
189.
190.
191.
192.
Cowsert LM, Monia BP, Hendry BM: Evidence of a role for Ki-Ras in the stimulated proliferation of renal fibroblasts. J Am Soc Nephrol 10: 1186 1192, 1999 Okada H, Watanabe Y, Inoue T, Kobayashi T, Kikuta T, Kanno Y, Ban S, Suzuki H: Angiotensin II type 1 receptor blockade attenuates renal fibrogenesis in an immunemediated nephritic kidney through counter-activation of angiotensin II type 2 receptor. Biochem Biophys Res Commun 314: 403 408, 2004 Yang L, Besschetnova TY, Brooks CR, Shah JV, Bonventre JV: Epithelial cell cycle arrest in G2/M mediates kidney fibrosis after injury. Nat Med 16: 535543, 2010 Zeisberg M, Strutz F, Muller GA: Renal fibrosis: An update. Curr Opin Nephrol Hypertens 10: 315320, 2001 Wang S, LaPage J, Hirschberg R: Proteinuria and progression of chronic renal disease. Kidney Blood Press Res 23: 167169, 2000 Baines RJ, Brunskill NJ: The molecular interactions between filtered proteins and proximal tubular cells in proteinuria. Nephron Exp Nephrol 110: e67 e71, 2008 Schlondorff DO: Overview of factors contributing to the pathophysiology of progressive renal disease. Kidney Int 74: 860 866, 2008 Pichler R, Giachelli C, Young B, Alpers CE, Couser WG, Johnson RJ: The pathogenesis of tubulointerstitial disease associated with glomerulonephritis: The glomerular cytokine theory. Miner Electrolyte Metab 21: 317327, 1995 Hirschberg R, Wang S: Proteinuria and growth factors in the development of tubulointerstitial injury and scarring in kidney disease. Curr Opin Nephrol Hypertens 14: 4352, 2005 Rosivall L, Mirzahosseini S, Toma I, Sipos A, Peti-Peterdi J: Fluid flow in the juxtaglomerular interstitium visualized in vivo. Am J Physiol Renal Physiol 291: F1241F1247, 2006 Rohatgi R, Flores D: Intratubular hydrodynamic forces influence tubulointerstitial fibrosis in the kidney. Curr Opin Nephrol Hypertens 19: 6571, 2010 Sanz AB, Sanchez-Nino MD, Ramos AM, Moreno JA, Santamaria B, Ruiz-Ortega M, Egido J, Ortiz A: NF-{kappa}B in renal inflammation. J Am Soc Nephrol 21: 1254 1262, 2010 Abbate M, Zoja C, Remuzzi G: How does proteinuria cause progressive renal damage? J Am Soc Nephrol 17: 2974 2984, 2006 Sanchez-Lopez E, Rayego S, RodriguesDiez R, Rodriguez JS, Rodriguez-Vita J, Carvajal G, Aroeira LS, Selgas R, Mezzano SA, Ortiz A, Egido J, Ruiz-Ortega M: CTGF promotes inflammatory cell infiltration of the renal interstitium by activating NF-kap-
193.
194.
195.
196.
197.
198.
199.
200.
201.
202.
203.
paB. J Am Soc Nephrol 20: 15131526, 2009 Pontrelli P, Ursi M, Ranieri E, Capobianco C, Schena FP, Gesualdo L, Grandaliano G: CD40L proinflammatory and profibrotic effects on proximal tubular epithelial cells: Role of NF-kappaB and lyn. J Am Soc Nephrol 17: 627 636, 2006 Li XC, Zhuo JL: Nuclear factor-kappaB as a hormonal intracellular signaling molecule: focus on angiotensin II-induced cardiovascular and renal injury. Curr Opin Nephrol Hypertens 17: 37 43, 2008 Esteban V, Lorenzo O, Ruperez M, Suzuki Y, Mezzano S, Blanco J, Kretzler M, Sugaya T, Egido J, Ruiz-Ortega M: Angiotensin II, via AT1 and AT2 receptors and NF-kappaB pathway, regulates the inflammatory response in unilateral ureteral obstruction. J Am Soc Nephrol 15: 1514 1529, 2004 Zoja C, Garcia PB, Remuzzi G: The role of chemokines in progressive renal disease. Front Biosci 14: 18151822, 2009 Semedo P, Correa-Costa M, Antonio Cenedeze M, Maria Avancini Costa Malheiros D, Antonia dos Reis M, Shimizu MH, Seguro AC, Pacheco-Silva A, Saraiva Camara NO: Mesenchymal stem cells attenuate renal fibrosis through immune modulation and remodeling properties in a rat remnant kidney model. Stem Cells 27: 30633073, 2009 Shimizu H, Maruyama S, Yuzawa Y, Kato T, Miki Y, Suzuki S, Sato W, Morita Y, Maruyama H, Egashira K, Matsuo S: Antimonocyte chemoattractant protein-1 gene therapy attenuates renal injury induced by protein-overload proteinuria. J Am Soc Nephrol 14: 1496 1505, 2003 Tashiro K, Tamada S, Kuwabara N, Komiya T, Takekida K, Asai T, Iwao H, Sugimura K, Matsumura Y, Takaoka M, Nakatani T, Miura K: Attenuation of renal fibrosis by proteasome inhibition in rat obstructive nephropathy: Possible role of nuclear factor kappaB. Int J Mol Med 12: 587592, 2003 Gong R, Rifai A, Tolbert EM, Biswas P, Centracchio JN, Dworkin LD: Hepatocyte growth factor ameliorates renal interstitial inflammation in rat remnant kidney by modulating tubular expression of macrophage chemoattractant protein-1 and RANTES. J Am Soc Nephrol 15: 2868 2881, 2004 Ka SM, Huang XR, Lan HY, Tsai PY, Yang SM, Shui HA, Chen A: Smad7 gene therapy ameliorates an autoimmune crescentic glomerulonephritis in mice. J Am Soc Nephrol 18: 17771788, 2007 Lan HY: Smad7 as a therapeutic agent for chronic kidney diseases. Front Biosci 13: 4984 4992, 2008 Tan X, Wen X, Liu Y: Paricalcitol inhibits renal inflammation by promoting vitamin D receptor-mediated sequestration of NF-
204.
205.
206.
207.
208.
209.
210.
211.
212.
213.
214.
215.
kappaB signaling. J Am Soc Nephrol 19: 17411752, 2008 Takase O, Hirahashi J, Takayanagi A, Chikaraishi A, Marumo T, Ozawa Y, Hayashi M, Shimizu N, Saruta T: Gene transfer of truncated IkappaBalpha prevents tubulointerstitial injury. Kidney Int 63: 501513, 2003 Herrero-Fresneda I, Torras J, Franquesa M, Vidal A, Cruzado JM, Lloberas N, Fillat C, Grinyo JM: HGF gene therapy attenuates renal allograft scarring by preventing the profibrotic inflammatory-induced mechanisms. Kidney Int 70: 265274, 2006 Han SY, Kim CH, Kim HS, Jee YH, Song HK, Lee MH, Han KH, Kim HK, Kang YS, Han JY, Kim YS, Cha DR: Spironolactone prevents diabetic nephropathy through an anti-inflammatory mechanism in type 2 diabetic rats. J Am Soc Nephrol 17: 1362 1372, 2006 Kim KH, Lee ES, Cha SH, Park JH, Park JS, Chang YC, Park KK: Transcriptional regulation of NF-kappaB by ring type decoy oligodeoxynucleotide in an animal model of nephropathy. Exp Mol Pathol 86: 114 120, 2009 Peng M, Jarett L, Meade R, Madaio MP, Hancock WW, George AL Jr., Neilson EG, Gasser DL: Mutant prenyltransferase-like mitochondrial protein (PLMP) and mitochondrial abnormalities in kd/kd mice. Kidney Int 66: 20 28, 2004 Chevalier RL, Forbes MS: Generation and evolution of atubular glomeruli in the progression of renal disorders. J Am Soc Nephrol 19: 197206, 2008 Nadasdy T, Laszik Z, Blick KE, Johnson DL, Silva FG: Tubular atrophy in the end-stage kidney: A lectin and immunohistochemical study. Hum Pathol 25: 2228, 1994 Docherty NG, OSullivan OE, Healy DA, Fitzpatrick JM, Watson RW: Evidence that inhibition of tubular cell apoptosis protects against renal damage and development of fibrosis following ureteric obstruction. Am J Physiol Renal Physiol 290: F4 F13, 2006 Attanasio M, Uhlenhaut NH, Sousa VH, OToole JF, Otto E, Anlag K, Klugmann C, Treier AC, Helou J, Sayer JA, Seelow D, Nurnberg G, Becker C, Chudley AE, Nurnberg P, Hildebrandt F, Treier M: Loss of GLIS2 causes nephronophthisis in humans and mice by increased apoptosis and fibrosis. Nat Genet 39: 1018 1024, 2007 Neilson EG: Plasticity, nuclear diapause, and a requiem for the terminal differentiation of epithelia. J Am Soc Nephrol 18: 19951998, 2007 Chase LG, Ulloa-Montoya F, Kidder BL, Verfaillie CM: Islet-derived fibroblast-like cells are not derived via epithelial-mesenchymal transition from Pdx-1 or insulin-positive cells. Diabetes 56: 37, 2007 Taura K, Miura K, Iwaisako K, Osterreicher
J Am Soc Nephrol 21: 1819 1834, 2010
1831
BRIEF REVIEW
www.jasn.org
216.
217.
218.
219.
220.
221.
222.
223.
224.
225.
CH, Kodama Y, Penz-Osterreicher M, Brenner DA: Hepatocytes do not undergo epithelial-mesenchymal transition in liver fibrosis in mice. Hepatology 51: 10271036, 2010 Flier SN, Tanjore H, Kokkotou EG, Sugimoto H, Zeisberg M, Kalluri R: Identification of epithelial to mesenchymal transition as a novel source of fibroblasts in intestinal fibrosis. J Biol Chem 285: 2020220212, 2010 Zeisberg M, Yang C, Martino M, Duncan MB, Rieder F, Tanjore H, Kalluri R: Fibroblasts derive from hepatocytes in liver fibrosis via epithelial to mesenchymal transition. J Biol Chem 282: 2333723347, 2007 Tanjore H, Xu XC, Polosukhin VV, Degryse AL, Li B, Han W, Sherrill TP, Plieth D, Neilson EG, Blackwell TS, Lawson WE: Contribution of epithelial-derived fibroblasts to bleomycin-induced lung fibrosis. Am J Respir Crit Care Med 180: 657 665, 2009 Kim KK, Kugler MC, Wolters PJ, Robillard L, Galvez MG, Brumwell AN, Sheppard D, Chapman HA: Alveolar epithelial cell mesenchymal transition develops in vivo during pulmonary fibrosis and is regulated by the extracellular matrix. Proc Natl Acad Sci U S A 103: 13180 13185, 2006 Kim KK, Wei Y, Szekeres C, Kugler MC, Wolters PJ, Hill ML, Frank JA, Brumwell AN, Wheeler SE, Kreidberg JA, Chapman HA: Epithelial cell alpha3beta1 integrin links beta-catenin and Smad signaling to promote myofibroblast formation and pulmonary fibrosis. J Clin Invest 119: 213224, 2009 Zeisberg EM, Potenta S, Xie L, Zeisberg M, Kalluri R: Discovery of endothelial to mesenchymal transition as a source for carcinoma-associated fibroblasts. Cancer Res 67: 1012310128, 2007 Kokudo T, Suzuki Y, Yoshimatsu Y, Yamazaki T, Watabe T, Miyazono K: Snail is required for TGFbeta-induced endothelialmesenchymal transition of embryonic stem cell-derived endothelial cells. J Cell Sci 121: 331733124, 2008 Vongwiwatana A, Tasanarong A, Rayner DC, Melk A, Halloran PF: Epithelial to mesenchymal transition during late deterioration of human kidney transplants: The role of tubular cells in fibrogenesis. Am J Transplant 5: 13671374, 2005 Robertson H, Ali S, McDonnell BJ, Burt AD, Kirby JA: Chronic renal allograft dysfunction: The role of T cell-mediated tubular epithelial to mesenchymal cell transition. J Am Soc Nephrol 15: 390 397, 2004 Hertig A, Anglicheau D, Verine J, Pallet N, Touzot M, Ancel PY, Mesnard L, Brousse N, Baugey E, Glotz D, Legendre C, Rondeau E, Xu-Dubois YC: Early epithelial phenotypic changes predict graft fibrosis. J Am Soc Nephrol 19: 1584 1591, 2008
226. Vitalone MJ, OConnell PJ, Jimenez-Vera E, Yuksel A, Wavamunno M, Fung CL, Chapman JR, Nankivell BJ: Epithelial-tomesenchymal transition in early transplant tubulointerstitial damage. J Am Soc Nephrol 19: 15711583, 2008 227. Hildebrandt F, Attanasio M, Otto E: Nephronophthisis: Disease mechanisms of a ciliopathy. J Am Soc Nephrol 20: 2335, 2009 228. Sun S, Ning X, Zhang Y, Lu Y, Nie Y, Han S, Liu L, Du R, Xia L, He L, Fan D: Hypoxiainducible factor-1alpha induces Twist expression in tubular epithelial cells subjected to hypoxia, leading to epithelial-tomesenchymal transition. Kidney Int 75: 1278 1287, 2009 229. Zeng R, Yao Y, Han M, Zhao X, Liu XC, Wei J, Luo Y, Zhang J, Zhou J, Wang S, Ma D, Xu G: Biliverdin reductase mediates hypoxia-induced EMT via PI3-kinase and Akt. J Am Soc Nephrol 19: 380 387, 2008 230. Gunaratnam L, Bonventre JV: HIF in kidney disease and development. J Am Soc Nephrol 20: 18771887, 2009 231. Okada H, Danoff TM, Kalluri R, Neilson EG: Early role of Fsp1 in epithelial-mesenchymal transformation. Am J Physiol 273: F563F574, 1997 232. Docherty NG, OSullivan OE, Healy DA, Murphy M, ONeill AJ, Fitzpatrick JM, Watson RW: TGF-beta1-induced EMT can occur independently of its proapoptotic effects and is aided by EGF receptor activation. Am J Physiol Renal Physiol 290: F1202F1212, 2006 233. Ardura JA, Rayego-Mateos S, Ramila D, Ruiz-Ortega M, Esbrit P: Parathyroid hormone-related protein promotes epithelialmesenchymal transition. J Am Soc Nephrol 21: 237248, 2010 234. Oldfield MD, Bach LA, Forbes JM, NikolicPaterson D, McRobert A, Thallas V, Atkins RC, Osicka T, Jerums G, Cooper ME: Advanced glycation end products cause epithelial-myofibroblast transdifferentiation via the receptor for advanced glycation end products (RAGE). J Clin Invest 108: 18531863, 2001 235. Zhang Y, Kong J, Deb DK, Chang A, Li YC: Vitamin d receptor attenuates renal fibrosis by suppressing the renin-angiotensin system. J Am Soc Nephrol 21: 966 973, 2010 236. Venkov CD, Link AJ, Jennings JL, Plieth D, Inoue T, Nagai K, Xu C, Dimitrova YN, Rauscher FJ, Neilson EG: A proximal activator of transcription in epithelial-mesenchymal transition. J Clin Invest 117: 482 491, 2007 237. Boutet A, De Frutos CA, Maxwell PH, Mayol MJ, Romero J, Nieto MA: Snail activation disrupts tissue homeostasis and induces fibrosis in the adult kidney. EMBO J 25: 56035613, 2006 238. Kida Y, Asahina K, Teraoka H, Gitelman I, Sato T: Twist relates to tubular epithelial-
239.
240.
241.
242.
243.
244.
245.
246.
247.
248.
249.
250.
251.
mesenchymal transition and interstitial fibrogenesis in the obstructed kidney. J Histochem Cytochem 55: 661 673, 2007 Mao H, Li Z, Zhou Y, Zhuang S, An X, Zhang B, Chen W, Nie J, Wang Z, Borkan SC, Wang Y, Yu X: HSP72 attenuates renal tubular cell apoptosis and interstitial fibrosis in obstructive nephropathy. Am J Physiol Renal Physiol 295: F202F214, 2008 Thiery JP, Acloque H, Huang RY, Nieto MA: Epithelial-mesenchymal transitions in development and disease. Cell 139: 871 890, 2009 Yang J, Liu Y: Blockage of tubular epithelial to myofibroblast transition by hepatocyte growth factor prevents renal interstitial fibrosis. J Am Soc Nephrol 13: 96 107, 2002 Dworkin LD, Gong R, Tolbert E, Centracchio J, Yano N, Zanabli AR, Esparza A, Rifai A: Hepatocyte growth factor ameliorates progression of interstitial fibrosis in rats with established renal injury. Kidney Int 65: 409 419, 2004 Li Y, Tan X, Dai C, Stolz DB, Wang D, Liu Y: Inhibition of integrin-linked kinase attenuates renal interstitial fibrosis. J Am Soc Nephrol 20: 19071918, 2009 Liu M, Gu M, Wu Y, Zhu P, Zhang W, Yin C, Zhang WJ: Therapeutic effect of Y-27632 on chronic allograft nephropathy in rats. J Surg Res 157: e117 e127, 2009 Gai Z, Zhou G, Itoh S, Morimoto Y, Tanishima H, Hatamura I, Uetani K, Ito M, Muragaki Y: Trps1 functions downstream of Bmp7 in kidney development. J Am Soc Nephrol 20: 24032411, 2009 Gai Z, Zhou G, Gui T, Itoh S, Oikawa K, Uetani K, Muragaki Y: Trps1 haploinsufficiency promotes renal fibrosis by increasing Arkadia expression. J Am Soc Nephrol 21: 1468 1476, 2010 Haruna Y, Kashihara N, Satoh M, Tomita N, Namikoshi T, Sasaki T, Fujimori T, Xie P, Kanwar YS: Amelioration of progressive renal injury by genetic manipulation of Klotho gene. Proc Natl Acad Sci U S A 104: 23312336, 2007 Lieberthal W, Levine JS: The role of the mammalian target of rapamycin (mTOR) in renal disease. J Am Soc Nephrol 20: 2493 2502, 2009 Lindop GB, Gibson IW, Downie TT, Vass D, Cohen EP: The glomerulo-tubular junction: A target in renal diseases. J Pathol 197: 13, 2002 Benigni A, Gagliardini E, Remuzzi A, Corna D, Remuzzi G: Angiotensin-converting enzyme inhibition prevents glomerular-tubule disconnection and atrophy in passive Heymann nephritis, an effect not observed with a calcium antagonist. Am J Pathol 159: 17431750, 2001 Smeets B, Angelotti ML, Rizzo P, Dijkman H, Lazzeri E, Mooren F, Ballerini L, Parente E, Sagrinati C, Mazzinghi B, Ronconi E, Becherucci F, Benigni A, Steenbergen E,
1832
J Am Soc Nephrol 21: 1819 1834, 2010
www.jasn.org
BRIEF REVIEW
252.
253.
254.
255.
256.
257.
258.
259.
260.
261.
262.
263.
Lasagni L, Remuzzi G, Wetzels J, Romagnani P: Renal progenitor cells contribute to hyperplastic lesions of podocytopathies and crescentic glomerulonephritis. J Am Soc Nephrol 20: 25932603, 2009 Lazzeri E, Crescioli C, Ronconi E, Mazzinghi B, Sagrinati C, Netti GS, Angelotti ML, Parente E, Ballerini L, Cosmi L, Maggi L, Gesualdo L, Rotondi M, Annunziato F, Maggi E, Lasagni L, Serio M, Romagnani S, Vannelli GB, Romagnani P: Regenerative potential of embryonic renal multipotent progenitors in acute renal failure. J Am Soc Nephrol 18: 3128 3138, 2007 Kim D, Dressler GR: Nephrogenic factors promote differentiation of mouse embryonic stem cells into renal epithelia. J Am Soc Nephrol 16: 35273534, 2005 de Groh ED, Swanhart LM, Cosentino CC, Jackson RL, Dai W, Kitchens CA, Day BW, Smithgall TE, Hukriede NA: Inhibition of histone deacetylase expands the renal progenitor cell population. J Am Soc Nephrol 21: 794 802, 2010 Kelly KJ, Burford JL, Dominguez JH: Postischemic inflammatory syndrome: A critical mechanism of progression in diabetic nephropathy. Am J Physiol Renal Physiol 297: F923F931, 2009 Basile DP: Rarefaction of peritubular capillaries following ischemic acute renal failure: A potential factor predisposing to progressive nephropathy. Curr Opin Nephrol Hypertens 13: 17, 2004 Kang DH, Kanellis J, Hugo C, Truong L, Anderson S, Kerjaschki D, Schreiner GF, Johnson RJ: Role of the microvascular endothelium in progressive renal disease. J Am Soc Nephrol 13: 806 816, 2002 Eardley KS, Kubal C, Zehnder D, Quinkler M, Lepenies J, Savage CO, Howie AJ, Kaur K, Cooper MS, Adu D, Cockwell P: The role of capillary density, macrophage infiltration and interstitial scarring in the pathogenesis of human chronic kidney disease. Kidney Int 74: 495504, 2008 Li J, Qu X, Bertram JF: Endothelial-myofibroblast transition contributes to the early development of diabetic renal interstitial fibrosis in streptozotocin-induced diabetic mice. Am J Pathol 175: 1380 1388, 2009 Fine LG, Norman JT: Chronic hypoxia as a mechanism of progression of chronic kidney diseases: From hypothesis to novel therapeutics. Kidney Int 74: 867 872, 2008 Nangaku M, Eckardt KU: Hypoxia and the HIF system in kidney disease. J Mol Med 85: 13251330, 2007 Norman JT, Stidwill R, Singer M, Fine LG: Angiotensin II blockade augments renal cortical microvascular pO2 indicating a novel, potentially renoprotective action. Nephron Physiol 94: 39 46, 2003 Fujimoto S, Satoh M, Nagasu H, Horike H, Sasaki T, Kashihara N: Azelnidipine exerts renoprotective effects by improvement of
264.
265.
266.
267.
268.
269.
270.
271.
272.
273.
274.
renal microcirculation in angiotensin II infusion rats. Nephrol Dial Transplant 24: 36513658, 2009 Neuhofer W, Pittrow D: Role of endothelin and endothelin receptor antagonists in renal disease. Eur J Clin Invest 36 [Suppl 3]: 78 88, 2006 Gagliardini E, Corna D, Zoja C, Sangalli F, Carrara F, Rossi M, Conti S, Rottoli D, Longaretti L, Remuzzi A, Remuzzi G, Benigni A: Unlike each drug alone, lisinopril if combined with avosentan promotes regression of renal lesions in experimental diabetes. Am J Physiol Renal Physiol 297: F1448 F1456, 2009 Kimura K, Iwano M, Higgins DF, Yamaguchi Y, Nakatani K, Harada K, Kubo A, Akai Y, Rankin EB, Neilson EG, Haase VH, Saito Y: Stable expression of HIF-1alpha in tubular epithelial cells promotes interstitial fibrosis. Am J Physiol Renal Physiol 295: F1023 F1029, 2008 Long DA, Mu W, Price KL, Roncal C, Schreiner GF, Woolf AS, Johnson RJ: Vascular endothelial growth factor administration does not improve microvascular disease in the salt-dependent phase of post-angiotensin II hypertension. Am J Physiol Renal Physiol 291: F1248 F1254, 2006 Haroun MK, Jaar BG, Hoffman SC, Comstock GW, Klag MJ, Coresh J: Risk factors for chronic kidney disease: A prospective study of 23,534 men and women in Washington County, Maryland. J Am Soc Nephrol 14: 2934 2941, 2003 OHare AM, Choi AI, Bertenthal D, Bacchetti P, Garg AX, Kaufman JS, Walter LC, Mehta KM, Steinman MA, Allon M, McClellan WM, Landefeld CS: Age affects outcomes in chronic kidney disease. J Am Soc Nephrol 18: 2758 2765, 2007 Vikse BE, Irgens LM, Leivestad T, Hallan S, Iversen BM: Low birth weight increases risk for end-stage renal disease. J Am Soc Nephrol 19: 151157, 2008 Migeon BR: X inactivation, female mosaicism, and sex differences in renal diseases. J Am Soc Nephrol 19: 20522059, 2008 Melamed ML, Astor B, Michos ED, Hostetter TH, Powe NR, Muntner P: 25-Hydroxyvitamin D levels, race, and the progression of kidney disease. J Am Soc Nephrol 20: 26312639, 2009 Chen Y, Mahata M, Rao F, Khandrika S, Courel M, Fung MM, Zhang K, Stridsberg M, Ziegler MG, Hamilton BA, Lipkowitz MS, Taupenot L, Nievergelt C, Mahata SK, OConnor DT: Chromogranin A regulates renal function by triggering Weibel-Palade body exocytosis. J Am Soc Nephrol 20: 16231632, 2009 Ryu S, Chang Y, Woo HY, Kim SG, Kim DI, Kim WS, Suh BS, Choi NK, Lee JT: Changes in body weight predict CKD in healthy men. J Am Soc Nephrol 19: 1798 1805, 2008
275. Matsushita K, Selvin E, Bash LD, Franceschini N, Astor BC, Coresh J: Change in estimated GFR associates with coronary heart disease and mortality. J Am Soc Nephrol 20: 26172624, 2009 276. Kottgen A, Pattaro C, Boger CA, Fuchsberger C, Olden M, Glazer NL, Parsa A, Gao X, Yang Q, Smith AV, OConnell JR, Li M, Schmidt H, Tanaka T, Isaacs A, Ketkar S, Hwang SJ, Johnson AD, Dehghan A, Teumer A, Pare G, Atkinson EJ, Zeller T, Lohman K, Cornelis MC, Probst-Hensch NM, Kronenberg F, Tonjes A, Hayward C, Aspelund T, Eiriksdottir G, Launer LJ, Harris TB, Rampersaud E, Mitchell BD, Arking DE, Boerwinkle E, Struchalin M, Cavalieri M, Singleton A, Giallauria F, Metter J, de Boer IH, Haritunians T, Lumley T, Siscovick D, Psaty BM, Zillikens MC, Oostra BA, Feitosa M, Province M, de Andrade M, Turner ST, Schillert A, Ziegler A, Wild PS, Schnabel RB, Wilde S, Munzel TF, Leak TS, Illig T, Klopp N, Meisinger C, Wichmann HE, Koenig W, Zgaga L, Zemunik T, Kolcic I, Minelli C, Hu FB, Johansson A, Igl W, Zaboli G, Wild SH, Wright AF, Campbell H, Ellinghaus D, Schreiber S, Aulchenko YS, Felix JF, Rivadeneira F, Uitterlinden AG, Hofman A, Imboden M, Nitsch D, Brandstatter A, Kollerits B, Kedenko L, Magi R, Stumvoll M, Kovacs P, Boban M, Campbell S, Endlich K, Volzke H, Kroemer HK, Nauck M, Volker U, Polasek O, Vitart V, Badola S, Parker AN, Ridker PM, Kardia SL, Blankenberg S, Liu Y, Curhan GC, Franke A, Rochat T, Paulweber B, Prokopenko I, Wang W, Gudnason V, Shuldiner AR, Coresh J, Schmidt R, Ferrucci L, Shlipak MG, van Duijn CM, Borecki I, Kra mer BK, Rudan I, Gyllensten U, Wilson JF, Witteman JC, Pramstaller PP, Rettig R, Hastie N, Chasman DI, Kao WH, Heid IM, Fox CS: New loci associated with kidney function and chronic kidney disease. Nat Genet 42: 376 384, 2010 277. Hung AM, Crawford DC, Griffin MR, Brown-Gentry K, Lipkowitz MS, Siew ED, Cavanaugh K, Lewis JB, Ikizler TA: CRP polymorphisms and progression of chronic kidney disease in African Americans. Clin J Am Soc Nephrol 5: 24 33, 2010 278. Rao M, Wong C, Kanetsky P, Girndt M, Stenvinkel P, Reilly M, Raj DS: Cytokine gene polymorphism and progression of renal and cardiovascular diseases. Kidney Int 72: 549 556, 2007 279. Yoshida T, Kato K, Fujimaki T, Yokoi K, Oguri M, Watanabe S, Metoki N, Yoshida H, Satoh K, Aoyagi Y, Nishigaki Y, Tanaka M, Nozawa Y, Kimura G, Yamada Y: Association of genetic variants with chronic kidney disease in Japanese individuals. Clin J Am Soc Nephrol 4: 883 890, 2009 280. Kottgen A, Glazer NL, Dehghan A, Hwang SJ, Katz R, Li M, Yang Q, Gudnason V, Launer LJ, Harris TB, Smith AV, Arking DE, Astor BC,
J Am Soc Nephrol 21: 1819 1834, 2010
1833
BRIEF REVIEW
www.jasn.org
Boerwinkle E, Ehret GB, Ruczinski I, Scharpf RB, Ida Chen YD, de Boer IH, Haritunians T, Lumley T, Sarnak M, Siscovick D, Benjamin EJ, Levy D, Upadhyay A, Aulchenko YS, Hofman A, Rivadeneira F, Uitterlinden AG, van Duijn CM, Chasman DI, Pare G, Ridker PM, Kao WH, Witteman JC, Coresh J, Shlipak MG, Fox CS: Multiple loci associated with indices of renal function and chronic kidney disease. Nat Genet 41: 712717, 2009 281. Kottgen A, Hwang SJ, Larson MG, Van Eyk JE, Fu Q, Benjamin EJ, Dehghan A, Glazer NL, Kao WH, Harris TB, Gudnason
V, Shlipak MG, Yang Q, Coresh J, Levy D, Fox CS: Uromodulin levels associate with a common UMOD variant and risk for incident CKD. J Am Soc Nephrol 21: 337344, 2010 282. Kottgen A, Kao WH, Hwang SJ, Boerwinkle E, Yang Q, Levy D, Benjamin EJ, Larson MG, Astor BC, Coresh J, Fox CS: Genomewide association study for renal traits in the Framingham Heart and Atherosclerosis Risk in Communities Studies. BMC Med Genet 9: 49, 2008 283. Ho JJ, Marsden PA: Dicer cuts the kidney. J Am Soc Nephrol 19: 20432046, 2008
284. Carthew RW, Sontheimer EJ: Origins and Mechanisms of miRNAs and siRNAs. Cell 136: 642 655, 2009 285. Chung AC, Huang XR, Meng X, Lan HY: miR-192 Mediates TGF-{beta}/Smad3Driven Renal Fibrosis. J Am Soc Nephrol 21: 13171325, 2010 286. Kato M, Zhang J, Wang M, Lanting L, Yuan H, Rossi JJ, Natarajan R: MicroRNA-192 in diabetic kidney glomeruli and its function in TGF-beta-induced collagen expression via inhibition of E-box repressors. Proc Natl Acad Sci U S A 104: 34323437, 2007
1834
J Am Soc Nephrol 21: 1819 1834, 2010

Mechanism of Tubulointerstitial Fibrosis

Uploaded by

Document Information

Original Title

Copyright

Available Formats

Share this document

Share or Embed Document

Sharing Options

Did you find this document useful?

Is this content inappropriate?

Copyright:

Available Formats

Mechanism of Tubulointerstitial Fibrosis

Uploaded by

Copyright:

Available Formats

BRIEF REVIEW

Mechanisms of Tubulointerstitial Fibrosis

THE EXTRACELLULAR MATRIX

Journal of the American Society of Nephrology

Journal of the American Society of Nephrology

Tubular epithelial cells spark the progression of fibrogenesis to their own

Mechanisms of Tubulointerstitial Fibrosis

Journal of the American Society of Nephrology

GENETIC PREDISPOSITION TO RENAL PROGRESSION

Mechanisms of Tubulointerstitial Fibrosis

evant for patients with chronic kidney disease.

Journal of the American Society of Nephrology

J Am Soc Nephrol 21: 1819 1834, 2010

J Am Soc Nephrol 21: 1819 1834, 2010

Mechanisms of Tubulointerstitial Fibrosis

Journal of the American Society of Nephrology

J Am Soc Nephrol 21: 1819 1834, 2010

J Am Soc Nephrol 21: 1819 1834, 2010

Mechanisms of Tubulointerstitial Fibrosis

Journal of the American Society of Nephrology

J Am Soc Nephrol 21: 1819 1834, 2010

J Am Soc Nephrol 21: 1819 1834, 2010

Mechanisms of Tubulointerstitial Fibrosis

Journal of the American Society of Nephrology

J Am Soc Nephrol 21: 1819 1834, 2010

J Am Soc Nephrol 21: 1819 1834, 2010

Mechanisms of Tubulointerstitial Fibrosis

Journal of the American Society of Nephrology

J Am Soc Nephrol 21: 1819 1834, 2010

You might also like