Matrix metalloproteinases in kidney homeostasis and

diseases
Roderick J. Tan and Youhua Liu
Am J Physiol Renal Physiol 302:F1351-F1361, 2012. First published 4 April 2012;
doi: 10.1152/ajprenal.00037.2012

You might find this additional info useful...

This article cites 154 articles, 57 of which you can access for free at:
http://ajprenal.physiology.org/content/302/11/F1351.full#ref-list-1
This article has been cited by 1 other HighWire-hosted articles:

Downloaded from http://ajprenal.physiology.org/ at University of South Dakota on November 18, 2012

http://ajprenal.physiology.org/content/302/11/F1351#cited-by
Updated information and services including high resolution figures, can be found at:
http://ajprenal.physiology.org/content/302/11/F1351.full
Additional material and information about American Journal of Physiology - Renal Physiology can be
found at:
http://www.the-aps.org/publications/ajprenal

This information is current as of November 18, 2012.

American Journal of Physiology - Renal Physiology publishes original manuscripts on a broad range of subjects
relating to the kidney, urinary tract, and their respective cells and vasculature, as well as to the control of body fluid
volume and composition. It is published 24 times a year (twice monthly) by the American Physiological Society,
9650 Rockville Pike, Bethesda MD 20814-3991. Copyright © 2012 the American Physiological Society. ESSN:
1522-1466. Visit our website at http://www.the-aps.org/.
Am J Physiol Renal Physiol 302: F1351–F1361, 2012.
First published April 4, 2012; doi:10.1152/ajprenal.00037.2012. Review

Matrix metalloproteinases in kidney homeostasis and diseases

Roderick J. Tan1 and Youhua Liu2
1
Renal-Electrolyte Division, Department of Medicine, University of Pittsburgh School of Medicine and 2Department
of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, Pennsylvania
Submitted 20 January 2012; accepted in final form 3 April 2012

Tan RJ, Liu Y. Matrix metalloproteinases in kidney homeostasis and diseases.

Am J Physiol Renal Physiol 302: F1351–F1361, 2012. First published April 4,
2012; doi:10.1152/ajprenal.00037.2012.—Matrix metalloproteinases (MMPs) are a

Downloaded from http://ajprenal.physiology.org/ at University of South Dakota on November 18, 2012

family of zinc-dependent endopeptidases that have been increasingly linked to both
normal physiology and abnormal pathology in the kidney. Collectively able to
degrade all components of the extracellular matrix, MMPs were originally thought
to antagonize the development of fibrotic diseases solely through digestion of
excessive matrix. However, increasing evidence has shown that MMPs play a wide
variety of roles in regulating inflammation, epithelial-mesenchymal transition, cell
proliferation, angiogenesis, and apoptosis. We now have robust evidence for MMP
dysregulation in a multitude of renal diseases including acute kidney injury,
diabetic nephropathy, glomerulonephritis, inherited kidney disease, and chronic
allograft nephropathy. The goal of this review is to summarize current findings
regarding the role of MMPs in kidney diseases as well as the mechanisms of action
of this family of proteases.
MMP; fibrosis; epithelial-mesenchymal transition; inflammation; apoptosis

THE MATRIX METALLOPROTEINASES (MMPs) are a large family of
zinc-dependent endopeptidases that are collectively capable of
proteolyzing all components of the extracellular matrix (ECM)
(15, 99). The first discovery of MMPs was originally reported
by Gross and Lapiere (38) when they described collagenase
activity in metamorphosing tadpoles. Since then, the number of
known MMPs as well as their characterized functions have
risen dramatically (83, 139). It is now accepted that MMPs
play a multitude of roles in regulating a diverse array of
biological processes such as embryonic development, tissue
homeostasis, tumorigenesis, and organ fibrogenesis (15, 97).
Initially thought to degrade only ECM proteins, MMPs are
increasingly known to be able to cleave a wide variety of
substrates, which range from cell surface receptors and adhe-
sion molecules to growth factors and cytokines. This broad
spectrum of substrates enables MMPs to be a critical player not
only in regulating ECM remodeling but also in controlling
many cell behaviors such as cell proliferation, migration,
differentiation, angiogenesis, and apoptosis (37, 83). Over the
last decade, thanks to the availability of many genetically
modified mice (both knockout and transgenic) and specific
pharmacological inhibitors, our understanding of the biology
of MMPs in vivo has substantially evolved and improved.
Many studies have provided significant insights into the exact
roles of specific MMPs in regulating physiological homeostasis
and pathological disorders.
MMPs are expressed in both developing and adult kidneys,
and they are implicated in regulating nephron formation and
the pathogenesis of kidney diseases, as nicely summarized
previously in a comprehensive review (15). In light of their
Address for reprint requests and other correspondence: Y. Liu, Dept. of
Pathology, Univ. of Pittsburgh, S-405 Biomedical Science Tower, 200 Lothrop
St., Pittsburgh, PA 15261 (e-mail: liuy@upmc.edu).
http://www.ajprenal.org 1931-857X/12 Copyright © 2012 the American Physiological Society
proteolytic potential, MMPs are traditionally conceived as
antifibrotic players in the development and progression of
chronic kidney diseases (CKD), in which tissue fibrosis is the
common outcome. This assumption, however, has been chal-
lenged recently, and a new paradigm is emerging that MMPs
actually play a critical role in the initiation of fibrotic kidney
disorders. Here, we review the biology of MMPs, with empha-
sis on their role and potential mechanisms in the development
of kidney diseases.
Biology of MMPs
Structure and classification. All MMPs, with some modifi-
cations, share a core set of basic structural domains. As shown
in Fig. 1, the prototype MMP consists of a prodomain, a
catalytic domain, a hinge region, and a hemopexin-like domain
(15, 87). As secreted proteins, MMPs are synthesized with a
signal peptide responsible for directing secretion out of the cell.
The prodomain consists of a conserved cysteine residue that
prevents binding and cleavage of the substrate, while the catalytic
domain contains a binding site comprised of three histidines that
coordinate with a single zinc and is responsible for the enzymatic
activity of the protease. MMP-2 and -9 have a series of fibronectin
repeats in this domain as well. A flexible hinge region then
separates the catalytic domain from a four-bladed propeller-
shaped hemopexin domain. It is felt that substrate specificity as
well as endogenous inhibitor binding are influenced by speci-
ficities of each MMP’s catalytic and hemopexin domains (37,
139). Some MMPs remain tethered to the cell via transmem-
brane and cytoplasmic domains at the C terminus. At least one
MMP (MMP-23) has a type II transmembrane domain near the
N terminus and also possesses a cysteine-rich region and
immunoglobulin-like domain (87, 139). The crystal structure
of active human MMP-1 containing many of the domains
described above is shown in Fig. 2.
F1351
Review
F1352 MMPs IN KIDNEY DISEASES
Fig. 1. Domain structure of the matrix metalloproteinase (MMP)
family. The MMPs are structurally composed of similar modular
domains. The presence or absence of these domains, along with
their substrate specificity, has been used to classify the MMPs into
several subgroups. S, signal peptide; Pro, prodomain; Cat, catalytic
domain; h, hinge region; F, furin sensitive cleavage site; Fn,
fibronectin-like repeat; II, type II transmembrane domain; G,
glycosylphosphatidylinositol (GPI)-anchor.
MMPs are traditionally classified according to their structure
and/or ECM substrate specificity. The collagenases (MMP-1,
MMP-8, and MMP-13) can degrade native collagen and are
often hypothesized to be antifibrotic. Stromelysins (MMP-3,
MMP-10, and MMP-11) share structural similarity with the
collagenases but are unable to degrade native collagen. As their
name implies, the gelatinases (MMP-2, MMP-9) cleave dena-
tured collagen (gelatin) as well as type IV collagen in basement
membranes. Matrilysins (MMP-7, MMP-26) degrade ECM
components such as laminin and entactin. The membrane-type
MMPs (MT-MMPs) are embedded in the plasma membrane of
the cells via type I or II domains or glycosylphosphatidylinosi-
tol (GPI)-anchors. Other MMPs do not conform easily to
classification and include macrophage elastase (MMP-12) and
Fig. 2. Crystal structure of MMP-1. Active human MMP-1 is shown as a
ribbon diagram. The structure was determined with the help of a single amino
acid mutation to create an inhibitor-free structure that should closely represent
the active form. Four calcium ions and 2 zinc ions are part of the structure.
Helices (hA, hB, hC) and strands (s1–5) are labeled, as are the 4 propeller-
shaped blades of the hemopexin domain (bI–IV). Published with permission (54).
AJP-Renal Physiol • doi:10.1152/ajprenal.00037.2012 • www.ajprenal.org
Downloaded from http://ajprenal.physiology.org/ at University of South Dakota on November 18, 2012
epilysin (MMP-28) (83, 95). Substrate specificities are sum-
marized in Table 1.
Transcriptional regulation. Regulation of MMPs at the level
of gene expression has been reviewed elsewhere (29, 74), and
it involves activating protein (AP)-1 and AP-2, PEA3, NF-␬B,
Smad, and STAT transcription factors and their cognate bind-
ing sites. Of note, some of the MMPs, including MMP-7 and
MMP-9, are regulated through canonical Wnt/␤-catenin sig-
naling (45, 140), a pathway that has been demonstrated to be
associated with kidney development and injury (41, 44). Stud-
ies from our laboratory have also demonstrated that tissue
plasminogen activator (tPA) leads to an enhanced transcription
of MMP-9 in renal interstitial fibroblasts, through a pathway
dependent on cell-surface LDL receptor-related protein-1
(LRP-1) and on Erk-1/2 activation. This activation is indepen-
dent of the enzymatic activity of tPA (49, 148).
Posttranslational activation. The MMPs are synthesized as
inactive zymogens maintained by a conserved cysteine residue
that interacts with the zinc in the active site and prevents a
catalytic water molecule from associating with the metal ion,
rendering the protease inactive (87). Activation requires disrup-
tion of this so-called “cysteine switch,” which can be accom-
plished through proteolytic cleavage of the propeptide by trypsin,
plasmin, or even other MMPs (137). In addition, several MMPs
contain a furin-sensitive cleavage site for the propeptide, indicat-
ing intracellular activation of these enzymes (87).
MMP-9 has a unique relationship with neutrophil gelatinase-
associated lipocalin (NGAL), as they are coexpressed by neu-
trophils and can interact with each other. This interaction
prevents the degradation of MMP-9, potentially prolonging its
lifespan and effects. As NGAL has long been recognized as a
potential biomarker for kidney injury, detectable in the urine of
affected individuals, it is conceivable that the interaction of
MMP-9 and NGAL could play a specific role in prolonging
MMP action in renal pathology (130), and this hypothesis
deserves further attention in the future.
An interesting story of MMPs with nitrosative and oxidative
stress has also emerged. The cysteine switch contains a thiol
residue that can be altered by reactive oxygen species (ROS)
and reactive nitrogen species (RNS), causing dissociation from
the catalytic site, leading to enzyme activation (96, 137). Such
regulation is tightly controlled, as it is shown that at lower
concentrations, MMP-7 is activated by hypochlorous acid
(from myeloperoxidase), whereas at higher concentrations
MMP-7 is inactivated, apparently through oxidative cross-
linking of amino acids affecting the active site (31, 32). These
 Review
MMPs IN KIDNEY DISEASES F1353
Table 1. MMPs and their substrates
MMP Alternate Names Selected Substrates Selected Reference(s)

MMP-1 Collagenase-1 Collagen I, II, III, entactin, perlectan, IGF-BP-2 and -3, pro-IL-1␤, IL-1␤ 38
MMP-2 Gelatinase A Gelatin, collagen IV, V, XI, laminin, aggrecan, pro-TGF-␤, pro-TNF-␣, 18, 131
IGFBP-3 and -5
MMP-3 Stromelysin-1 Aggrecan, laminin, fibronectin, fibrinogen, MCP-1 to -4, pro-MMP-1, -3, -7, 56, 126
-8, -9, -13
MMP-7 Matrilysin Plasminogen, pro-␣-defensin, FasL, pro-TNF-␣, E-cadherin, syndecan, 45, 78, 99, 140
pro-MMPs
MMP-8 Collagenase-2 Collagen I-III, VII, X, aggrecan, fibronectin, pro-TNF-␣, IGF-BP, MCP-1, 136
angiotensin
MMP-9 Gelatinase B Gelatin, collagen IV, V, XI, pro-IL-8, Pro-TNF-␣, pro-TGF-␤, pro-MMP-2, 49, 146, 153

Downloaded from http://ajprenal.physiology.org/ at University of South Dakota on November 18, 2012

-9, -13
MMP-10 Stromelysin-2 Gelatins, fibronectin, proteoglycan, pro-MMP-1, -8, -10 93, 106
MMP-11 Stromelysin-3 Fibronectin, laminin, aggrecan, IGFBP-1 84
MMP-12 Metalloelastase Elastin, fibronectin, laminin, plasminogen, pro-TNF-␣ 46
MMP-13 Collagenase-3 Collagen I, II, III, entactin, aggrecan, tenascin, pro-TNF-␣, pro-MMP-9, -13 62, 63
MMP-14 MT1-MMP Collagen I, II, III, laminin, fibronectin, pro-MMP-2, -13, CD44, tissue 87
transglutaminase
MMP-15 MT2-MMP Pro-MMP-2, pro-TNF-␣, tissue transglutaminase 1
MMP-16 MT3-MMP Collagen III, pro-MMP-2, pro-TNF-␣, tissue transglutaminase
MMP-17 MT4-MMP Gelatin, fibronectin, fibrin, pro-MMP-2, ADAMTS-4, TIMPs, pro-TNF-␣ 118
MMP-18 Collagenase-4 Collagen I, II, III 129
MMP-19 Stromelysin-4 Collagen IV, gelatin, laminin 10, 85
MMP-20 Enamelysin Amelogenin, aggrecan, cartilage oligomeric matrix protein (COMP) 73
MMP-21 Gelatin, ␣-1-antitrypsin 76
MMP-23 May be similar to stromelysins and collagenases 138
MMP-24 MT5-MMP Pro-MMP-2
MMP-25 MT6-MMP Collagen IV, gelatin, fibrin, fironectin, pro-MMP-2 and -9, TIMPs, uPAR 118
MMP-26 Matrilysin-2 Collagen IV, fibronectin, fibrin, fibrinogen, pro-MMP-9 98, 115
MMP-27 Gelatin, casein
MMP-28 Epilysin Neural cell adhesion molecule (NCAM), casein 53
MMP, matrix metalloproteinase. Data were compiled with the noted references as well as previous reviews (37, 95). uPAR, urokinase plasminogen activator
receptor; IGF-BP, insulin-like growth factor binding protein.

findings suggest that although the cysteine switch thiol is the
preferred site of oxidative alteration, at times of greater oxidant
production, the enzyme is inactivated, possibly preventing
overactivity. Such fine-tuning of MMP activity by oxidative
stress underscores the complexity of MMP regulation. Whether
such mechanisms play a role in renal pathology remains to be
determined.
Natural inhibitors. MMP activity is regulated by a family of
naturally occurring, endogenous inhibitors known as tissue inhib-
itors of metalloproteinases (TIMPs). The four known TIMPs have
varying specificities for different MMPs but collectively can
inhibit all of them. Generally, TIMPs combine in 1:1 stoichiom-
etry with MMPs and associate with the catalytic and hemopexin
domains to cause inhibition (87). However, TIMPs also partici-
pate in metalloproteinase activation, as in the case of TIMP-2-
associated activation of MMP-2 in the presence of MT1-MMP.
There is now evidence that TIMPs can participate in other non-
traditional functions such as cell proliferation, apoptosis, and
angiogenesis, and that a role of MMPs is to modulate TIMP
signaling via sequestering a limited pool of TIMPs (82, 87).
MMPs in Renal Pathology
While the temporal and spatial expression of MMPs in the
kidney has not been completely characterized, numerous stud-
ies have demonstrated dysregulation of MMPs in a wide
variety of kidney disorders. Figure 3 compiles the distribution
and expression profile of MMPs along the nephron in normal
and pathological conditions. Ample evidence also suggests that
MMPs could be potential targets for therapeutic intervention in
kidney disease. Table 2 summarizes the effect of these MMP-
specific interventions in renal pathology.
Acute kidney injury. Acute kidney injury (AKI) is usually
caused by exposure to ischemia-reperfusion injury or nephro-
toxins and is a major cause of morbidity and mortality (142).
Urinary MMP-9, in combination with other markers, could
serve as a biomarker of AKI (40). A wide variety of AKI
models have characterized an increase in the expression of
MMP-2 and MMP-9 as well as MMP-7 (8, 11, 91). Although
methods to decrease MMP activity generally reduce injury in
the majority of experimental models, at least one study shows
that MMP-9 knockouts did worse, due to a diminished anti-
apoptotic signaling through stem cell factor (Table 2).
Diabetic nephropathy. Diabetic nephropathy is the most
common cause of end-stage kidney disease in the industrialized
world and is characterized clinically by albuminuria and pro-
gressive renal failure, and pathologically by mesangial expan-
sion, glomerulosclerosis, tubular atrophy, and interstitial fibro-
sis (87). Collectively, the majority of studies show increased
MMP-2, MMP-8, and MMP-9 in the serum and urine from
diabetic patients (36, 60, 65, 108, 125, 126, 135). In fact, a
positive correlation exists between degree of albuminuria and
levels of urinary MMP-9 (125). In addition, urinary excretion
of NGAL is concomitantly increased with MMP-9, which is
particularly intriguing since NGAL is not only a proposed
biomarker of kidney injury but can aid in sustained activation
of MMPs (127). An elevated serum MMP-7 level may also be
a biomarker, as it is inversely correlated with renal function in
proteinuric diabetic patients (5). Tubular expression of MMP-7

AJP-Renal Physiol • doi:10.1152/ajprenal.00037.2012 • www.ajprenal.org

Review
F1354 MMPs IN KIDNEY DISEASES

Fig. 3. Expression profile of MMP/tissue inhibitors of metallo-

proteinases (TIMPs) along the nephron. The various MMPs and
their inhibitors have unique expression profiles along the
nephron. Currently known localizations are shown. An asterisk
(*) denotes upregulation in renal pathological conditions, while
a dagger (†) denotes downregulation in disease states. PCT,

Downloaded from http://ajprenal.physiology.org/ at University of South Dakota on November 18, 2012

proximal convoluted tubule; LOH, loop of Henle; DCT, distal
convoluted tubule; CD, collecting duct. Data are compiled from
many original studies.

is induced in human kidney biopsies from patients with dia-
betic nephropathy, and its level is closely correlated with
␤-catenin abundance (45). Observations have also described
downregulation of MMP-1 and TIMPs, with upregulation of
membrane-type MMPs (21, 60, 108, 109).
The role of MMPs in the pathogenesis of diabetic nephrop-
athy is controversial and inconsistent. In addition, experimental
models do not always recapitulate clinical findings, as recently
reviewed (126). These contradictions could be caused by
differences in animal strains, samples obtained, and cell types
examined, as well as the fact that diabetes treatment affects
MMP expression (126). Some models show that decreased
MMP activity, particularly of MMP-2 and MMP-9, ameliorate
kidney lesions (107, 114, 144, 150), whereas in other models
maintenance of MMPs, namely, MMP-1 and in some cases
even MMP-9, is associated with improvement (see Table 2) (4,
34). Similarly contradictory, TIMP-3 was elevated in diabetes,
but TIMP-3 null mice actually had worsened fibrosis and
increased activation of MMP-2 (55, 57). Collectively, these
data highlight the complexities of MMP pathobiology and the
continued need for mechanistic studies.
Nondiabetic glomerular disease. MMP levels are altered in
other nondiabetic glomerular diseases. Single nucleotide poly-
morphisms in MMP-14 confer risk for developing focal seg-

Table 2. Effect of MMP manipulations in kidney diseases

Intervention Model System Overall Effect Specific Findings Reference(s)

Acute kidney injury

MMP-2 null Mouse, I/R Improved Reduced incidence of AKI 59, 61
MMP-9 null Mouse, I/R Improved Prevented loss of microvascular density 61
MMP-9 null Mouse, I/R Worsened Tubular apoptosis, delayed recovery 11
MMP inhibition Rat, I/R Improved Decreased AKI, apoptosis, and cytokine release 51
MMP inhibition Mouse, I/R Improved Decreased histological damage 91
Diabetic nephropathy
MMP inhibition Human, diabetes Improved Decreased proteinuria at 3 mo 2
MMP-1 transgenic Mouse, diabetes Improved Decreased fibrosis 4
MMP inhibition Rat, diabetes Improved Reduced proteinuria/glomerulosclerosis/fibrosis 144
Interstitial fibrosis
TIMP-1 null Mouse, UUO No change Compensatory TIMP-3 upregulation 57
TIMP-1 overexpression Mouse, UUO Worsened Increased fibrosis and inflammation 13
TIMP-3 null Mouse, aging, UUO Worsened Increased fibrosis 55
MMP-9 null Mouse, UUO Improved Reduced fibrosis and EMT 141
MMP-2 inhibition Mouse, UUO Worsened Reduced inflammation, accelerated fibrosis 90
Inherited diseases
MMP inhibition Rat, PKD Improved Decreased cyst number 92
MMP gene deletion or inhibition Mouse, Alport’s Stage-specific Early inhibition attenuated disease, late inhibition 153
worsened disease
Glomerulonephritis
Doxycycline Rat, IC nephritis Improved Decreased proliferative lesions, IgG/C3 deposits 110
MMP inhibition Rats, MPGN Improved Decreased mesangial proliferation, fibrosis 119
MMP inhibition Rats, MPGN Improved Decreased collagen, ␣-SMA expression 81
MMP-9 or -13 null FSGS Improved Decreased collagen IV and proteinuria 111
TIMP, tissue inhibitor of metalloproteinase; I/R, ischemia-reperfusion injury; AKI, acute kidney injury; UUO, unilateral ureteral obstruction; PKD, polycystic
kidney disease; EMT, epithelial-mesenchymal transition; MPGN, membranoproliferative glomerulonephritis; FSGS, focal segmental glomerulosclerosis;
␣-SMA, ␣-smooth muscle actin.

AJP-Renal Physiol • doi:10.1152/ajprenal.00037.2012 • www.ajprenal.org


MMPs IN KIDNEY DISEASES
mental glomerulosclerosis (FSGS), although the underlying
mechanism is unknown (86). Patients with FSGS, minimal
change disease, membranous nephropathy, human immunode-
ficiency virus (HIV)-associated nephropathy, as well as anti-
neutrophil cytoplasmic antibody (ANCA)-associated vasculi-
tis, each had unique expression patterns of MMP-2 and
MMP-9 (3, 9, 24, 112, 113). Increased glomerular MMP-9 was
found in lupus nephritis, IgA nephropathy, Henoch-Schoenlein
Purpura (HSP), and postinfectious glomerulonephritis (134).
MMP-7 is induced in renal tubular epithelium of the kidneys in
FSGS and IgA nephropathy (45). MMP-3 is upregulated in
HSP and ANCA vasculitis (113, 115).
Experimentally, MMP-9 is upregulated in models of FSGS,
lupus nephritis, and Thy1.1 nephritis, a model for mem-
branoproliferative glomerulonephritis (MPGN) (69, 81, 128,
132). However, impaired resolution of disease appears to be
associated with a paradoxical decrease in MMP-9 late in the
course of Thy1.1 nephritis (128). Meanwhile, MMP-2 is in-
creased in both lupus and MPGN (81, 119, 133). A few studies
utilizing both selective and nonselective MMP inhibitors in
these models appear to ameliorate renal injury (Table 2).
Inherited kidney disease. Polycystic kidney disease (PKD) is
the most common inherited kidney disorder and has been
associated with MMP dysregulation. In serum of PKD patients,
there is an increase in TIMP-1, MMP-1, MMP-9, and type IV
collagen (a target of MMP-9) compared with controls (88).
There is also dramatic upregulation of MMP-7 associated with
expression of Wnt in PKD (120). As Wnt/␤-catenin signaling
is activated in tubular injury, it now appears that MMP-7 is a
target of this pathological signaling. MMP-14 is also noted in
cyst-lining epithelia in experimental PKD, and MMP inhibitor
therapy decreases cyst formation (92).
Alport syndrome (AS) is characterized by a mutation in colla-
gen IV, which may lead to altered basement membrane proteol-
ysis. Upregulation of MMP-2, -3, and -9 occurred in both human
AS and in animal models, and each MMP could digest AS-
derived basement membrane in vitro. Interestingly, early MMP
inhibition before onset of proteinuria attenuates renal lesions
while inhibition after proteinuria accelerates disease progression
(153). Numerous other MMPs are upregulated in AS, but their
roles have yet to be determined (22, 79, 103).
Chronic allograft nephropathy. Chronic rejection remains
the major limitation of renal transplantation, and circumstantial
AJP-Renal Physiol • doi:10.1152/ajprenal.00037.2012 • www.ajprenal.org
Review
F1355
evidence may indicate a role for MMPs. Numerous studies
have collectively identified increases in MMP-2, MMP-7,
MMP-8, and MMP-9, as well as TIMP-1 and -2 in cases of
allograft rejection (16, 27, 68, 80, 104, 105, 145). Interestingly,
polymorphisms in MMP-2 and -9 have been associated with
increased allograft survival (116), and the immunosuppressive
drug rapamycin inhibits MMP-9 expression while increasing
TIMP-1 (94). The potential mechanism of MMPs in rejection
remains an area of active investigation.
Mechanisms of MMP Action in Kidney Disease
Downloaded from http://ajprenal.physiology.org/ at University of South Dakota on November 18, 2012
As renal fibrosis is the common final outcome of CKD, it
was initially thought that MMPs may be globally protective
through antagonism of ECM accumulation. With an increas-
ingly expanding list of new MMP substrates, one has to
concede that MMP roles are not limited to digestion of matrix.
We have recently proposed that renal fibrosis appears to
progress through a series of phases including inflammation,
fibroblast/myofibroblast activation, matrix deposition, and fi-
brosis (70). It is conceivable that MMPs act at all levels of this
pathologic process, as well as in regulation of apoptosis and
angiogenesis (Figs. 4 and 5).
Inflammation. MMPs have critical roles in inflammatory cell
recruitment and chemotaxis, thereby regulating the inflamma-
tory response (Fig. 4). ICAM-1, a cell surface molecule pro-
moting leukocyte transmigration into tissues, is cleaved by
MMP-13 and MMP-14, suggesting an anti-inflammatory effect
(28, 124). Consistent with this, transgenic TIMP-1 overexpres-
sion does increase ICAM-1 in proximal tubular epithelium
(13). MMP-9 appears to play a role in self-propagating inflam-
mation by creating collagen fragments which are both chemot-
actic for neutrophils and stimulate them to release more
MMP-9 (146). Furthermore, MMP-9 mediates dendritic cell
(DC) migratory capacity and may also bind to cell surface
costimulatory molecules (50, 151). MMP-14 similarly appears
to have stimulatory roles in DC migration (35, 149). MMP-7
cleaves syndecans and their attached neutrophilic chemokines,
increasing inflammation by generating a chemotactic gradient
(64, 122). In addition, MMP-7 may promote inflammation by
facilitating the release of TNF-␣ from macrophages (43). This
MMP also cleaves E-cadherin and can regulate migration of DCs
containing the E-cadherin receptor, CD103 (␣E␤7-integrin) (75).
Fig. 4. Roles of MMPs in renal inflammation. MMPs, together
with TIMPs, regulate the activation, cytokine release, che-
motaxis, proliferation, and apoptosis of multiple inflammatory
cells.
Review
F1356
Fig. 5. Roles of MMPs in regulating epithelial-mesenchymal
transition (EMT) and renal fibrosis. MMPs are instrumental in
mediating tubular EMT via E-cadherin shedding and degrada-
tion of tubular basement membrane (TBM). MMPs, together
with TIMPs, also regulate the proliferation/apoptosis of inter-
stitial fibroblasts and glomerular mesangial cells. The proteo-
lytic products of matrix by MMPs also play a role in regulating
cellular activities such as endothelial cell growth and angiogenesis.
After chemotaxis, MMPs also regulate inflammatory cell
function. Gelatinase inhibition depresses lymphocyte prolifer-
ation in vitro and in vivo in experimental lung disease (12).
MMP-8 and -9 promote neutrophil survival (23, 58). Although
unproven, it has been proposed that MMPs could play a role in
exposing immunoreactive epitopes through cleavage of sub-
strates, leading to immune complex deposition (132). Regula-
tion can occur in both ways, as inflammatory cytokines mod-
ulate MMP production (89).
Inflammation mediates transplant rejection, but we can only
infer from nonrenal organ transplants the role of MMPs in the
kidney allografts. MMP-2 null mice have decreased T cell
alloreactivity and inflammatory cytokine release, while MMP-9
null mice have increased alloreactivity and cytokine release (14).
Broad-spectrum inhibition of MMPs leads to decreased inflam-
matory cell chemotaxis and improves cardiac graft survival (26).
However, these results may be tissue specific, as MMP-9 null
mice have improvement in survival of tracheal allografts (30).
Epithelial-mesenchymal transition. Epithelial-mesenchymal
transition (EMT) is the conversion of epithelium to a fibro-
blastic or myofibroblastic phenotype (71). Although the role of
EMT in renal fibrosis is controversial (102, 152), it is clear that
MMPs are a part of its regulation under experimental condi-
tions. MMP-2 localizes to areas of purported EMT, and, when
added to epithelial cultures, is sufficient to induce the expres-
sion of ␣-smooth muscle actin (␣-SMA), a marker of myofi-
broblasts (17). Furthermore, mice overexpressing MMP-2 in
proximal tubular epithelium induces EMT in a process char-
acterized by basement membrane disruption, leading to spon-
taneous tubular atrophy consistent with chronic kidney injury
(18). MMP-3 induces EMT in lung epithelia and promotes
fibrosis in vivo (147). MMP-9 could mediate EMT and in-
crease the migratory capacity of kidney epithelial cells (52,
123). Both MMP-3 and MMP-9 could individually induce
EMT in renal tubular cell cultures through cleavage of the
epithelial cell marker E-cadherin, which leads to activation of
␤-catenin (Fig. 5) (154). Consistent with these results, MMP-9
null mice have decreased EMT as measured by ␣-SMA and
decreased fibrosis after obstructive injury (141).
Cell proliferation and apoptosis. One of the interesting roles
discovered for MMPs is their involvement in the regulation of
cell proliferation and apoptosis (Fig. 5) (72, 100). MMPs
modulate cell proliferation primarily by indirect mechanisms.
For instance, MMP-9 is known to cleave membrane-bound
precursor proteins and release EGF-like ligands that subse-
AJP-Renal Physiol • doi:10.1152/ajprenal.00037.2012 • www.ajprenal.org
MMPs IN KIDNEY DISEASES
Downloaded from http://ajprenal.physiology.org/ at University of South Dakota on November 18, 2012
quently bind to the EGF receptor (100). Similarly, MMPs may
sequester TIMP-1, which could lead to inhibition of TIMP-1-
mediated fibroblast proliferation (72).
General MMP inhibition induces cell cycle arrest and apop-
tosis in mesangial cells in anti-Thy1.1 nephritis, while TIMP-1
similarly reduces apoptosis in mesangial cells under stress in
vitro (25, 67). MMP-7 can stimulate apoptosis through cleav-
ing and generating active soluble Fas ligand (101). On the
other hand, MMP-9 protects against apoptosis in acute kidney
injury through release of soluble stem cell factor (SCF), which
is the ligand for the c-kit tyrosine kinase receptor (11).
MMPs also modulate apoptosis via surprising mechanisms
separate from ectodomain shedding. MMP-8 null mice have
reduced neutrophil apoptosis via downregulation of caspases
(23). Interestingly, MMP-3 could actually translocate into the
nucleus of mammalian cells and stimulate apoptosis, and this
effect is dependent on retention of its catalytic activity (117).
Similarly, MMP-1 can localize to mitochondria and the nu-
cleus of various cell types, and knockdown of MMP-1 by small
interfering RNA (siRNA) sensitizes cells to apoptosis (66).
Further investigation is necessary to determine whether these
mechanisms impact the development of renal diseases.
ECM accumulation. Mesangial cell activation is believed to
be responsible for glomerulosclerosis development, and evi-
dence supports a pathogenic role for MMP-2, which is upregu-
lated in kidney fibrosis (18). MMP-2 production is increased in
mesangial cell cultures when exposed to components of the
ECM, including collagen 1, vitronectin, and fibronectin (77).
Cultured mesangial cells with high expression of MMP-2 have
greater proliferative capacity, are more motile, and produce
more ␣-SMA and collagen. This phenotype is reversed with
MMP-2-silencing RNA (131). Therefore, somewhat surpris-
ingly, MMP-2 can promote ECM production and accumulation
in kidney cells. Whether MMP-2 exerts its action via a direct
mechanism or an indirect one, such as promoting the release of
fibrogenic cytokines, remains to be determined.
ECM degradation. The excessive accumulation of ECM in
CKD is likely to involve aberrant levels of MMPs/TIMPs.
MMP-1 is downregulated in aging kidneys that have collagen
deposition (33). TIMP-1 overexpression occurs in fibrosis and can
promote fibroblast proliferation independently of MMP inhibition
(72). TIMP-1 deficiency does not prevent fibrosis, perhaps due to
the compensatory upregulation of other TIMPs (57).
While the degradation of ECM proteins by MMPs is beneficial
in that it reduces matrix accumulation, products of the degraded

MMPs IN KIDNEY DISEASES
ECM components may be capable of exerting some biological
actions. In this regard, a recent study shows that MMP-9 induced
EMT in vitro only when tubular cells were cultured on Matrigel
(141), suggesting that the proteolytic products of Matrigel by
MMP-9 are instrumental in promoting EMT. Therefore, increased
ECM degradation by MMPs, per se, may not necessarily translate
into a reduced fibrosis in CKD.
Degradation of the basement membrane, which is mainly
composed of type IV collagen and laminin, by MMPs such as
MMP-2, -7 and -9 could have a detrimental effect on the
integrity of renal parenchyma, thereby promoting the progres-
sion of CKD (Fig. 5). We have shown that although tPA can
lead to myofibroblast activation, serve as a mitogen for renal
fibroblasts, and promote their survival (42, 47, 48), its ability to
induce MMP-9, which in turn impairs tubular basement mem-
brane, probably plays a critical role in renal fibrogenesis (148).
Taken together, it is conceivable that the impact of ECM
degradation by MMPs in CKD is very complex and could be
either positive or negative to disease progression, depending on
MMP substrate specificities, disease models, and stages.
Vascular remodeling. MMPs also play an important role in
regulating endothelial cell behavior and vascular wall stiffness/
elasticity, thereby affecting vascular physiology and pathology.
It is well known that the proteolytic products of collagens by
MMPs, such as endostatin, are critical mediators in regulating
endothelial cell biology and angiogenesis (39, 143) (Fig. 5).
Angiostatin, generated by MMP-mediated degradation of col-
lagens, is antiangiogenic and is increased in ischemic injury
(8), consistent with a finding of reduced peritubular capillary
density in the outer medulla after acute renal failure (6). This
is accompanied by persistent hypoxia that can be detected up to
5 wk after ischemia-reperfusion injury (7). These changes in
renal vasculature could portend worsened renal prognosis and
increased vulnerability to future injuries.
More recent studies confirm increased perivascular MMP-2
and -9 after acute ischemic injury, and MMP-9 null mice
display reduced microvascular losses after ischemia, associated
with preserved VEGF levels (61). Vascular permeability is
reduced with inhibition of MMPs (121). Systemic effects are
also present, as CKD and dialysis patients have higher MMP-2
and -9 levels in extrarenal arteries, associated with calcification
and loss of elasticity. MMP inhibitors are capable of improving
vessel relaxation (19, 20).
Conclusion and Perspectives
Numerous inherited and acquired kidney diseases are char-
acterized by dysregulation of MMPs. In disorders ranging from
PKD to diabetic nephropathy to glomerulonephritis, MMPs are
upregulated (MMP-2, -7, and -9) as well as downregulated
(MMP-1). With the availability of MMP null animal models as
well as MMP-specific pharmacological inhibitors, we now
have the tools to carry out sophisticated mechanistic studies
that promise to provide greater insights into their exact roles in
renal pathophysiology.
Far from being simple enzymes whose only role is to maintain
ECM homeostasis, MMPs and their associated TIMPs are now
implicated in a diverse array of biological processes and cellular
events. MMPs can both promote and inhibit inflammation, acting
on events from chemotaxis to lymphocyte proliferation. Some
MMPs such as MMP-2, MMP-7, and MMP-9 seem necessary and
AJP-Renal Physiol • doi:10.1152/ajprenal.00037.2012 • www.ajprenal.org
Review
F1357
sufficient to induce EMT, a potentially significant step in fibrosis.
Surprising intracellular localization of MMPs and their roles in
regulating various cellular activities are just beginning to emerge.
The discovery of the specific roles for various MMPs does
suggest possible therapeutic options for patients with renal
diseases. However, as described in this review, the roles of
MMPs in kidney diseases are extremely complex, necessitating
that specific inhibitors target a single pathological MMP,
delivered at a particular point in time when that MMP is active,
without affecting MMPs important for normal tissue homeo-
stasis and function. Such therapy is challenging, even concep-
Downloaded from http://ajprenal.physiology.org/ at University of South Dakota on November 18, 2012
tually, and suggests that clinically useful MMP inhibitors are
still a distant reality.
Nonetheless, continued research is needed to further refine
our understanding of MMPs in specific renal pathologies.
Identification of the varying mechanisms of action of MMPs
will undoubtedly aid in our basic understanding of the patho-
genesis of various kidney disorders. Utilizing this knowledge
should renew the hope for targeted therapies that can be
beneficial for patients with kidney diseases in the future.
GRANTS
The work was supported by National Institute of Diabetes and Digestive
and Kidney Disease Grants DK064005 and DK091239.
DISCLOSURES
No conflicts of interest, financial or otherwise, are declared by the authors.
REFERENCES
1. Abraham R, Schafer J, Rothe M, Bange J, Knyazev P, Ullrich A.
Identification of MMP-15 as an anti-apoptotic factor in cancer cells. J
Biol Chem 280: 34123–34132, 2005.
2. Aggarwal HK, Jain D, Talapatra P, Yadav RK, Gupta T, Kathuria
KL. Evaluation of role of doxycycline (a matrix metalloproteinase
inhibitor) on renal functions in patients of diabetic nephropathy. Ren Fail
32: 941–946, 2010.
3. Ahuja TS, Gopalani A, Davies P, Ahuja H. Matrix metalloproteinase-9
expression in renal biopsies of patients with HIV-associated nephropa-
thy. Nephron Clin Pract 95: c100 –c104, 2003.
4. Aoyama T, Yamamoto S, Kanematsu A, Ogawa O, Tabata Y. Local
delivery of matrix metalloproteinase gene prevents the onset of renal
sclerosis in streptozotocin-induced diabetic mice. Tissue Eng 9: 1289 –
1299, 2003.
5. Ban CR, Twigg SM, Franjic B, Brooks BA, Celermajer D, Yue DK,
McLennan SV. Serum MMP-7 is increased in diabetic renal disease and
diabetic diastolic dysfunction. Diabetes Res Clin Pract 87: 335–341,
2010.
6. Basile DP, Donohoe D, Roethe K, Osborn JL. Renal ischemic injury
results in permanent damage to peritubular capillaries and influences
long-term function. Am J Physiol Renal Physiol 281: F887–F899, 2001.
7. Basile DP, Donohoe DL, Roethe K, Mattson DL. Chronic renal
hypoxia after acute ischemic injury: effects of L-arginine on hypoxia and
secondary damage. Am J Physiol Renal Physiol 284: F338 –F348, 2003.
8. Basile DP, Fredrich K, Weihrauch D, Hattan N, Chilian WM.
Angiostatin and matrix metalloprotease expression following ischemic
acute renal failure. Am J Physiol Renal Physiol 286: F893–F902, 2004.
9. Bauvois B, Mothu N, Nguyen J, Nguyen-Khoa T, Noel LH, Jungers
P. Specific changes in plasma concentrations of matrix metalloprotei-
nase-2 and -9, TIMP-1 and TGF-beta1 in patients with distinct types of
primary glomerulonephritis. Nephrol Dial Transplant 22: 1115–1122,
2007.
10. Beck IM, Ruckert R, Brandt K, Mueller MS, Sadowski T, Brauer R,
Schirmacher P, Mentlein R, Sedlacek R. MMP19 is essential for T cell
development and T cell-mediated cutaneous immune responses. PLoS
One 3: e2343, 2008.
11. Bengatta S, Arnould C, Letavernier E, Monge M, de Preneuf HM,
Werb Z, Ronco P, Lelongt B. MMP9 and SCF protect from apoptosis
in acute kidney injury. J Am Soc Nephrol 20: 787–797, 2009.
Review
F1358 MMPs IN KIDNEY DISEASES
12. Benson HL, Mobashery S, Chang M, Kheradmand F, Hong JS,
Smith GN, Shilling RA, Wilkes DS. Endogenous matrix metalloprotei-
nases 2 and 9 regulate activation of CD4⫹ and CD8⫹ T cells. Am J
Respir Cell Mol Biol 44: 700 –708, 2011.
13. Cai G, Zhang X, Hong Q, Shao F, Shang X, Fu B, Feng Z, Lin H,
Wang J, Shi S, Yin Z, Chen X. Tissue inhibitor of metalloproteinase-1
exacerbated renal interstitial fibrosis through enhancing inflammation.
Nephrol Dial Transplant 23: 1861–1875, 2008.
14. Campbell LG, Ramachandran S, Liu W, Shipley JM, Itohara S,
Rogers JG, Moazami N, Senior RM, Jaramillo A. Different roles for
matrix metalloproteinase-2 and matrix metalloproteinase-9 in the patho-
genesis of cardiac allograft rejection. Am J Transplant 5: 517–528, 2005.
15. Catania JM, Chen G, Parrish AR. Role of matrix metalloproteinases in
renal pathophysiologies. Am J Physiol Renal Physiol 292: F905–F911,
2007.
16. Chang HR, Kuo WH, Hsieh YS, Yang SF, Lin CC, Lee ML, Lian JD,
Chu SC. Circulating matrix metalloproteinase-2 is associated with cys-
tatin C level, posttransplant duration, and diabetes mellitus in kidney
transplant recipients. Transl Res 151: 217–223, 2008.
17. Cheng S, Lovett DH. Gelatinase A (MMP-2) is necessary and sufficient
for renal tubular cell epithelial-mesenchymal transformation. Am J
Pathol 162: 1937–1949, 2003.
18. Cheng S, Pollock AS, Mahimkar R, Olson JL, Lovett DH. Matrix
metalloproteinase 2 and basement membrane integrity: a unifying mech-
anism for progressive renal injury. FASEB J 20: 1898 –1900, 2006.
19. Chung AW, Yang HH, Kim JM, Sigrist MK, Chum E, Gourlay WA,
Levin A. Upregulation of matrix metalloproteinase-2 in the arterial
vasculature contributes to stiffening and vasomotor dysfunction in pa-
tients with chronic kidney disease. Circulation 120: 792–801, 2009.
20. Chung AW, Yang HH, Sigrist MK, Brin G, Chum E, Gourlay WA,
Levin A. Matrix metalloproteinase-2 and -9 exacerbate arterial stiffening
and angiogenesis in diabetes and chronic kidney disease. Cardiovasc Res
84: 494 –504, 2009.
21. Cornish TC, Bagnasco SM, Macgregor AM, Lu J, Selvin E, Ha-
lushka MK. Glomerular protein levels of matrix metalloproteinase-1 and
tissue inhibitor of metalloproteinase-1 are lower in diabetic subjects. J
Histochem Cytochem 57: 995–1001, 2009.
22. Cosgrove D, Meehan DT, Delimont D, Pozzi A, Chen X, Rodgers KD,
Tempero RM, Zallocchi M, Rao VH. Integrin alpha1beta1 regulates
matrix metalloproteinases via P38 mitogen-activated protein kinase in
mesangial cells: implications for Alport syndrome. Am J Pathol 172:
761–773, 2008.
23. Cox JH, Starr AE, Kappelhoff R, Yan R, Roberts CR, Overall CM.
Matrix metalloproteinase 8 deficiency in mice exacerbates inflammatory
arthritis through delayed neutrophil apoptosis and reduced caspase 11
expression. Arthritis Rheum 62: 3645–3655, 2010.
24. Czech KA, Bennett M, Devarajan P. Distinct metalloproteinase excre-
tion patterns in focal segmental glomerulosclerosis. Pediatr Nephrol 26:
2179 –2184, 2011.
25. Daniel C, Duffield J, Brunner T, Steinmann-Niggli K, Lods N, Marti
HP. Matrix metalloproteinase inhibitors cause cell cycle arrest and
apoptosis in glomerular mesangial cells. J Pharmacol Exp Ther 297:
57–68, 2001.
26. Eaton VL, Lerret NM, Velasquez-Lopera MM, John R, Caicedo M,
DeCresce RP, Jaramillo A. Enhanced allograft survival and modulation
of T-cell alloreactivity induced by inhibition of MMP/ADAM enzymatic
activity. Am J Transplant 8: 507–516, 2008.
27. Elster EA, Hawksworth JS, Cheng O, Leeser DB, Ring M, Tadaki
DK, Kleiner DE, Eberhardt JS, 3rd Brown TS, Mannon RB. Prob-
abilistic (Bayesian) modeling of gene expression in transplant glomeru-
lopathy. J Mol Diagn 12: 653–663, 2010.
28. Essick E, Sithu S, Dean W, D’Souza S. Pervanadate-induced shedding
of the intercellular adhesion molecule (ICAM)-1 ectodomain is mediated
by membrane type-1 matrix metalloproteinase (MT1-MMP). Mol Cell
Biochem 314: 151–159, 2008.
29. Fanjul-Fernandez M, Folgueras AR, Cabrera S, Lopez-Otin C.
Matrix metalloproteinases: evolution, gene regulation and functional
analysis in mouse models. Biochim Biophys Acta 1803: 3–19, 2010.
30. Fernandez FG, Campbell LG, Liu W, Shipley JM, Itohara S, Pat-
terson GA, Senior RM, Mohanakumar T, Jaramillo A. Inhibition of
obliterative airway disease development in murine tracheal allografts by
matrix metalloproteinase-9 deficiency. Am J Transplant 5: 671–683,
2005.
AJP-Renal Physiol • doi:10.1152/ajprenal.00037.2012 • www.ajprenal.org
31. Fu X, Kao JL, Bergt C, Kassim SY, Huq NP, d’Avignon A, Parks
WC, Mecham RP, Heinecke JW. Oxidative cross-linking of tryptophan
to glycine restrains matrix metalloproteinase activity: specific structural
motifs control protein oxidation. J Biol Chem 279: 6209 –6212, 2004.
32. Fu X, Kassim SY, Parks WC, Heinecke JW. Hypochlorous acid
generated by myeloperoxidase modifies adjacent tryptophan and glycine
residues in the catalytic domain of matrix metalloproteinase-7 (matrily-
sin): an oxidative mechanism for restraining proteolytic activity during
inflammation. J Biol Chem 278: 28403–28409, 2003.
33. Gagliano N, Arosio B, Santambrogio D, Balestrieri MR, Padoani G,
Tagliabue J, Masson S, Vergani C, Annoni G. Age-dependent expres-
sion of fibrosis-related genes and collagen deposition in rat kidney
cortex. J Gerontol A Biol Sci Med Sci 55: B365–B372, 2000.
Downloaded from http://ajprenal.physiology.org/ at University of South Dakota on November 18, 2012
34. 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.
35. Gawden-Bone C, Zhou Z, King E, Prescott A, Watts C, Lucocq J.
Dendritic cell podosomes are protrusive and invade the extracellular
matrix using metalloproteinase MMP-14. J Cell Sci 123: 1427–1437,
2010.
36. Gharagozlian S, Svennevig K, Bangstad HJ, Winberg JO, Kolset SO.
Matrix metalloproteinases in subjects with type 1 diabetes. BMC Clin
Pathol 9: 7, 2009.
37. Gialeli C, Theocharis AD, Karamanos NK. Roles of matrix metallo-
proteinases in cancer progression and their pharmacological targeting.
FEBS J 278: 16 –27, 2011.
38. Gross J. How tadpoles lose their tails: path to discovery of the first
matrix metalloproteinase. Matrix Biol 23: 3–13, 2004.
39. Hamano Y, Kalluri R. Tumstatin, the NC1 domain of alpha3 chain of
type IV collagen, is an endogenous inhibitor of pathological angiogenesis
and suppresses tumor growth. Biochem Biophys Res Commun 333:
292–298, 2005.
40. Han WK, Waikar SS, Johnson A, Betensky RA, Dent CL, Devarajan
P, Bonventre JV. Urinary biomarkers in the early diagnosis of acute
kidney injury. Kidney Int 73: 863–869, 2008.
41. Hao S, He W, Li Y, Ding H, Hou Y, Nie J, Hou FF, Kahn M, Liu Y.
Targeted inhibition of ␤-catenin/CBP signaling ameliorates renal inter-
stitial fibrosis. J Am Soc Nephrol 22: 1642–1653, 2011.
42. Hao S, Shen H, Hou Y, Mars WM, Liu Y. tPA is a potent mitogen for
renal interstitial fibroblasts: role of beta1 integrin/focal adhesion kinase
signaling. Am J Pathol 177: 1164 –1175, 2010.
43. Haro H, Crawford HC, Fingleton B, Shinomiya K, Spengler DM,
Matrisian LM. Matrix metalloproteinase-7-dependent release of tumor
necrosis factor-alpha in a model of herniated disc resorption. J Clin
Invest 105: 143–150, 2000.
44. He W, Dai C, Li Y, Zeng G, Monga SP, Liu Y. Wnt/␤-catenin
signaling promotes renal interstitial fibrosis. J Am Soc Nephrol 20:
765–776, 2009.
45. He W, Tan RJ, Li Y, Wang D, Nie J, Hou FF, Liu Y. Matrix
metalloproteinase-7 as a surrogate marker predicts renal Wnt/␤-catenin
activity in CKD. J Am Soc Nephrol 23: 294 –304, 2012.
46. Houghton AM, Quintero PA, Perkins DL, Kobayashi DK, Kelley
DG, Marconcini LA, Mecham RP, Senior RM, Shapiro SD. Elastin
fragments drive disease progression in a murine model of emphysema. J
Clin Invest 116: 753–759, 2006.
47. Hu K, Lin L, Tan X, Yang J, Bu G, Mars WM, Liu Y. tPA protects
renal interstitial fibroblasts and myofibroblasts from apoptosis. J Am Soc
Nephrol 19: 503–514, 2008.
48. Hu K, Wu C, Mars WM, Liu Y. Tissue-type plasminogen activator
promotes murine myofibroblast activation through LDL receptor-related
protein 1-mediated integrin signaling. J Clin Invest 117: 3821–3832,
2007.
49. Hu K, Yang J, Tanaka S, Gonias SL, Mars WM, Liu Y. Tissue-type
plasminogen activator acts as a cytokine that triggers intracellular signal
transduction and induces matrix metalloproteinase-9 gene expression. J
Biol Chem 281: 2120 –2127, 2006.
50. Hu Y, Ivashkiv LB. Costimulation of chemokine receptor signaling by
matrix metalloproteinase-9 mediates enhanced migration of IFN-alpha
dendritic cells. J Immunol 176: 6022–6033, 2006.
51. Ihtiyar E, Yasar NF, Erkasap N, Koken T, Tosun M, Oner S,
Erkasap S. Effects of doxycycline on renal ischemia reperfusion injury

MMPs IN KIDNEY DISEASES
induced by abdominal compartment syndrome. J Surg Res 167: 113–120,
2011.
52. Ikari A, Takiguchi A, Atomi K, Sato T, Sugatani J. Decrease in
claudin-2 expression enhances cell migration in renal epithelial Madin-
Darby canine kidney cells. J Cell Physiol 226: 1471–1478, 2011.
53. Illman SA, Lohi J, Keski-Oja J. Epilysin (MMP-28)–structure, expres-
sion and potential functions. Exp Dermatol 17: 897–907, 2008.
54. Iyer S, Visse R, Nagase H, Acharya KR. Crystal structure of an active
form of human MMP-1. J Mol Biol 362: 78 –88, 2006.
55. Kassiri Z, Oudit GY, Kandalam V, Awad A, Wang X, Ziou X, Maeda
N, Herzenberg AM, Scholey JW. Loss of TIMP3 enhances interstitial
nephritis and fibrosis. J Am Soc Nephrol 20: 1223–1235, 2009.
56. Kim EM, Hwang O. Role of matrix metalloproteinase-3 in neurodegen-
eration. J Neurochem 116: 22–32, 2011.
57. Kim H, Oda T, Lopez-Guisa J, Wing D, Edwards DR, Soloway PD,
Eddy AA. TIMP-1 deficiency does not attenuate interstitial fibrosis in
obstructive nephropathy. J Am Soc Nephrol 12: 736 –748, 2001.
58. Kolaczkowska E, Koziol A, Plytycz B, Arnold B, Opdenakker G.
Altered apoptosis of inflammatory neutrophils in MMP-9-deficient mice
is due to lower expression and activity of caspase-3. Immunol Lett 126:
73–82, 2009.
59. Kunugi S, Shimizu A, Kuwahara N, Du X, Takahashi M, Terasaki Y,
Fujita E, Mii A, Nagasaka S, Akimoto T, Masuda Y, Fukuda Y.
Inhibition of matrix metalloproteinases reduces ischemia-reperfusion
acute kidney injury. Lab Invest 91: 170 –180, 2011.
60. Lauhio A, Sorsa T, Srinivas R, Stenman M, Tervahartiala T, Sten-
man UH, Gronhagen-Riska C, Honkanen E. Urinary matrix metallo-
proteinase -8, -9, -14 and their regulators (TRY-1, TRY-2, TATI) in
patients with diabetic nephropathy. Ann Med 40: 312–320, 2008.
61. Lee SY, Horbelt M, Mang HE, Knipe NL, Bacallao RL, Sado Y,
Sutton TA. MMP-9 gene deletion mitigates microvascular loss in a
model of ischemic acute kidney injury. Am J Physiol Renal Physiol 301:
F101–F109, 2011.
62. Leeman MF, Curran S, Murray GI. The structure, regulation, and
function of human matrix metalloproteinase-13. Crit Rev Biochem Mol
Biol 37: 149 –166, 2002.
63. Li NG, Shi ZH, Tang YP, Wang ZJ, Song SL, Qian LH, Qian DW,
Duan JA. New hope for the treatment of osteoarthritis through selective
inhibition of MMP-13. Curr Med Chem 18: 977–1001, 2011.
64. Li Q, Park PW, Wilson CL, Parks WC. Matrilysin shedding of
syndecan-1 regulates chemokine mobilization and transepithelial efflux
of neutrophils in acute lung injury. Cell 111: 635–646, 2002.
65. Li Y, Kang YS, Dai C, Kiss LP, Wen X, Liu Y. Epithelial-to-
mesenchymal transition is a potential pathway leading to podocyte
dysfunction and proteinuria. Am J Pathol 172: 299 –308, 2008.
66. Limb GA, Matter K, Murphy G, Cambrey AD, Bishop PN, Morris
GE, Khaw PT. Matrix metalloproteinase-1 associates with intracellular
organelles and confers resistance to lamin A/C degradation during
apoptosis. Am J Pathol 166: 1555–1563, 2005.
67. Lin H, Chen X, Wang J, Yu Z. Inhibition of apoptosis in rat mesangial
cells by tissue inhibitor of metalloproteinase-1. Kidney Int 62: 60 –69,
2002.
68. Ling XB, Sigdel TK, Lau K, Ying L, Lau I, Schilling J, Sarwal MM.
Integrative urinary peptidomics in renal transplantation identifies bio-
markers for acute rejection. J Am Soc Nephrol 21: 646 –653, 2010.
69. Liu S, Li Y, Zhao H, Chen D, Huang Q, Wang S, Zou W, Zhang Y,
Li X, Huang H. Increase in extracellular cross-linking by tissue trans-
glutaminase and reduction in expression of MMP-9 contribute differen-
tially to focal segmental glomerulosclerosis in rats. Mol Cell Biochem
284: 9 –17, 2006.
70. Liu Y. Cellular and molecular mechanisms of renal fibrosis. Nat Rev
Nephrol 7: 684 –696, 2011.
71. Liu Y. New insights into epithelial-mesenchymal transition in kidney
fibrosis. J Am Soc Nephrol 21: 212–222, 2010.
72. Lu Y, Liu S, Zhang S, Cai G, Jiang H, Su H, Li X, Hong Q, Zhang
X, Chen X. Tissue inhibitor of metalloproteinase-1 promotes NIH3T3
fibroblast proliferation by activating p-Akt and cell cycle progression.
Mol Cells 31: 225–230, 2011.
73. Lu Y, Papagerakis P, Yamakoshi Y, Hu JC, Bartlett JD, Simmer JP.
Functions of KLK4 and MMP-20 in dental enamel formation. Biol Chem
389: 695–700, 2008.
74. Mancini A, Di Battista JA. Transcriptional regulation of matrix metal-
loprotease gene expression in health and disease. Front Biosci 11:
423–446, 2006.
AJP-Renal Physiol • doi:10.1152/ajprenal.00037.2012 • www.ajprenal.org
Review
F1359
75. Manicone AM, Huizar I, McGuire JK. Matrilysin (Matrix Metallopro-
teinase-7) regulates anti-inflammatory and antifibrotic pulmonary den-
dritic cells that express CD103 (alpha(E)beta(7)-integrin). Am J Pathol
175: 2319 –2331, 2009.
76. Marchenko GN, Marchenko ND, Strongin AY. The structure and
regulation of the human and mouse matrix metalloproteinase-21 gene and
protein. Biochem J 372: 503–515, 2003.
77. Martin J, Eynstone L, Davies M, Steadman R. Induction of metallo-
proteinases by glomerular mesangial cells stimulated by proteins of the
extracellular matrix. J Am Soc Nephrol 12: 88 –96, 2001.
78. McGuire JK, Li Q, Parks WC. Matrilysin (matrix metalloproteinase-7)
mediates E-cadherin ectodomain shedding in injured lung epithelium. Am
J Pathol 162: 1831–1843, 2003.
Downloaded from http://ajprenal.physiology.org/ at University of South Dakota on November 18, 2012
79. Meehan DT, Delimont D, Cheung L, Zallocchi M, Sansom SC,
Holzclaw JD, Rao V, Cosgrove D. Biomechanical strain causes mal-
adaptive gene regulation, contributing to Alport glomerular disease.
Kidney Int 76: 968 –976, 2009.
80. Metzger J, Chatzikyrkou C, Broecker V, Schiffer E, Jaensch L,
Iphoefer A, Mengel M, Mullen W, Mischak H, Haller H, Gwinner W.
Diagnosis of subclinical and clinical acute T-cell-mediated rejection in
renal transplant patients by urinary proteome analysis. Proteomics Clin
Appl 5: 322–333, 2011.
81. Mitani O, Katoh M, Shigematsu H. Participation of the matrix metal-
loproteinase inhibitor in Thy-1 nephritis. Pathol Int 54: 241–250, 2004.
82. Moore CS, Crocker SJ. An alternate perspective on the roles of TIMPs
and MMPs in Pathology. Am J Pathol 180: 12–16, 2012.
83. Morrison CJ, Butler GS, Rodriguez D, Overall CM. Matrix metallo-
proteinase proteomics: substrates, targets, and therapy. Curr Opin Cell
Biol 21: 645–653, 2009.
84. Motrescu ER, Rio MC. Cancer cells, adipocytes and matrix metallo-
proteinase 11: a vicious tumor progression cycle. Biol Chem 389:
1037–1041, 2008.
85. Muller M, Beck IM, Gadesmann J, Karschuk N, Paschen A, Proksch
E, Djonov V, Reiss K, Sedlacek R. MMP19 is upregulated during
melanoma progression and increases invasion of melanoma cells. Mod
Pathol 23: 511–521, 2010.
86. Munkert A, Helmchen U, Kemper MJ, Bubenheim M, Stahl RA,
Harendza S. Characterization of the transcriptional regulation of the
human MT1-MMP gene and association of risk reduction for focal-
segmental glomerulosclerosis with two functional promoter SNPs. Neph-
rol Dial Transplant 24: 735–742, 2009.
87. Nagase H, Visse R, Murphy G. Structure and function of matrix
metalloproteinases and TIMPs. Cardiovasc Res 69: 562–573, 2006.
88. Nakamura T, Ushiyama C, Suzuki S, Ebihara I, Shimada N, Koide
H. Elevation of serum levels of metalloproteinase-1, tissue inhibitor of
metalloproteinase-1 and type IV collagen, and plasma levels of metallo-
proteinase-9 in polycystic kidney disease. Am J Nephrol 20: 32–36, 2000.
89. Nee LE, McMorrow T, Campbell E, Slattery C, Ryan MP. TNF-alpha
and IL-1beta-mediated regulation of MMP-9 and TIMP-1 in renal prox-
imal tubular cells. Kidney Int 66: 1376 –1386, 2004.
90. Nishida M, Okumura Y, Ozawa S, Shiraishi I, Itoi T, Hamaoka K.
MMP-2 inhibition reduces renal macrophage infiltration with increased
fibrosis in UUO. Biochem Biophys Res Commun 354: 133–139, 2007.
91. Novak KB, Le HD, Christison-Lagay ER, Nose V, Doiron RJ, Moses
MA, Puder M. Effects of metalloproteinase inhibition in a murine model
of renal ischemia-reperfusion injury. Pediatr Res 67: 257–262, 2010.
92. Obermuller N, Morente N, Kranzlin B, Gretz N, Witzgall R. A
possible role for metalloproteinases in renal cyst development. Am J
Physiol Renal Physiol 280: F540 –F550, 2001.
93. Orbe J, Barrenetxe J, Rodriguez JA, Vivien D, Orset C, Parks WC,
Birkland TP, Serrano R, Purroy A, Martinez de Lizarrondo S,
Angles-Cano E, Paramo JA. Matrix metalloproteinase-10 effectively
reduces infarct size in experimental stroke by enhancing fibrinolysis via
a thrombin-activatable fibrinolysis inhibitor-mediated mechanism. Cir-
culation 124: 2909 –2919, 2011.
94. Osman B, Doller A, Akool el S, Holdener M, Hintermann E,
Pfeilschifter J, Eberhardt W. Rapamycin induces the TGFbeta1/Smad
signaling cascade in renal mesangial cells upstream of mTOR. Cell
Signal 21: 1806 –1817, 2009.
95. Overall CM. Molecular determinants of metalloproteinase substrate
specificity: matrix metalloproteinase substrate binding domains, mod-
ules, and exosites. Mol Biotechnol 22: 51–86, 2002.
Review
F1360 MMPs IN KIDNEY DISEASES
96. Owens MW, Milligan SA, Jourd’heuil D, Grisham MB. Effects of
reactive metabolites of oxygen and nitrogen on gelatinase A activity. Am
J Physiol Lung Cell Mol Physiol 273: L445–L450, 1997.
97. Pardo A, Selman M. Matrix metalloproteases in aberrant fibrotic tissue
remodeling. Proc Am Thorac Soc 3: 383–388, 2006.
98. Park HI, Lee S, Ullah A, Cao Q, Sang QX. Effects of detergents on
catalytic activity of human endometase/matrilysin 2, a putative cancer
biomarker. Anal Biochem 396: 262–268, 2010.
99. Parks WC, Wilson CL, Lopez-Boado YS. Matrix metalloproteinases as
modulators of inflammation and innate immunity. Nat Rev Immunol 4:
617–629, 2004.
100. Perng DW, Chang KT, Su KC, Wu YC, Chen CS, Hsu WH, Tsai
CM, Lee YC. Matrix metalloprotease-9 induces transforming growth
factor-beta(1) production in airway epithelium via activation of epider-
mal growth factor receptors. Life Sci 89: 204 –212, 2011.
101. Powell WC, Fingleton B, Wilson CL, Boothby M, Matrisian LM. The
metalloproteinase matrilysin proteolytically generates active soluble Fas
ligand and potentiates epithelial cell apoptosis. Curr Biol 9: 1441–1447,
1999.
102. Quaggin SE, Kapus A. Scar wars: mapping the fate of epithelial-
mesenchymal-myofibroblast transition. Kidney Int 80: 41–50, 2011.
103. Rao VH, Meehan DT, Delimont D, Nakajima M, Wada T, Gratton
MA, Cosgrove D. Role for macrophage metalloelastase in glomerular
basement membrane damage associated with Alport syndrome. Am J
Pathol 169: 32–46, 2006.
104. Rodder S, Scherer A, Korner M, Eisenberger U, Hertig A, Raulf F,
Rondeau E, Marti HP. Meta-analyses qualify metzincins and related
genes as acute rejection markers in renal transplant patients. Am J
Transplant 10: 286 –297, 2010.
105. Rodder S, Scherer A, Raulf F, Berthier CC, Hertig A, Couzi L,
Durrbach A, Rondeau E, Marti HP. Renal allografts with IF/TA
display distinct expression profiles of metzincins and related genes. Am
J Transplant 9: 517–526, 2009.
106. Rodriguez JA, Orbe J, Martinez de Lizarrondo S, Calvayrac O,
Rodriguez C, Martinez-Gonzalez J, Paramo JA. Metalloproteinases
and atherothrombosis: MMP-10 mediates vascular remodeling promoted
by inflammatory stimuli. Front Biosci 13: 2916 –2921, 2008.
107. Rodriguez WE, Tyagi N, Joshua IG, Passmore JC, Fleming JT,
Falcone JC, Tyagi SC. Pioglitazone mitigates renal glomerular vascular
changes in high-fat, high-calorie-induced type 2 diabetes mellitus. Am J
Physiol Renal Physiol 291: F694 –F701, 2006.
108. Romanic AM, Burns-Kurtis CL, Ao Z, Arleth AJ, Ohlstein EH.
Upregulated expression of human membrane type-5 matrix metallopro-
teinase in kidneys from diabetic patients. Am J Physiol Renal Physiol
281: F309 –F317, 2001.
109. Rysz J, Banach M, Stolarek RA, Pasnik J, Cialkowska-Rysz A,
Koktysz R, Piechota M, Baj Z. Serum matrix metalloproteinases
MMP-2 and MMP-9 and metalloproteinase tissue inhibitors TIMP-1 and
TIMP-2 in diabetic nephropathy. J Nephrol 20: 444 –452, 2007.
110. Saglam F, Celik A, Tayfur D, Cavdar Z, Yilmaz O, Sarioglu S,
Kolatan E, Oktay G, Camsari T. Decrease in cell proliferation by an
matrix metalloproteinase inhibitor, doxycycline, in a model of immune-
complex nephritis. Nephrology (Carlton) 15: 560 –567, 2010.
111. Sakamaki Y, Sasamura H, Hayashi K, Ishiguro K, Takaishi H,
Okada Y, D’Armiento JM, Saruta T, Itoh H. Absence of gelatinase
(MMP-9) or collagenase (MMP-13) attenuates adriamycin-induced albu-
minuria and glomerulosclerosis. Nephron Exp Nephrol 115: e22–e32,
2010.
112. Sanders JS, Huitema MG, Hanemaaijer R, van Goor H, Kallenberg
CG, Stegeman CA. Urinary matrix metalloproteinases reflect renal
damage in anti-neutrophil cytoplasm autoantibody-associated vasculitis.
Am J Physiol Renal Physiol 293: F1927–F1934, 2007.
113. Sanders JS, van Goor H, Hanemaaijer R, Kallenberg CG, Stegeman
CA. Renal expression of matrix metalloproteinases in human ANCA-
associated glomerulonephritis. Nephrol Dial Transplant 19: 1412–1419,
2004.
114. Sen U, Rodriguez WE, Tyagi N, Kumar M, Kundu S, Tyagi SC.
Ciglitazone, a PPARgamma agonist, ameliorates diabetic nephropathy in
part through homocysteine clearance. Am J Physiol Endocrinol Metab
295: E1205–E1212, 2008.
115. Shin JI, Song KS, Kim H, Cho NH, Kim J, Kim HS, Lee JS. The gene
expression profile of matrix metalloproteinases and their inhibitors in
children with Henoch-Schonlein purpura. Br J Dermatol 164: 1348 –
1355, 2011.
AJP-Renal Physiol • doi:10.1152/ajprenal.00037.2012 • www.ajprenal.org
116. Singh R, Srivastava P, Srivastava A, Mittal RD. Matrix metallopro-
teinase (MMP-9 and MMP-2) gene polymorphisms influence allograft
survival in renal transplant recipients. Nephrol Dial Transplant 25:
3393–3401, 2010.
117. Si-Tayeb K, Monvoisin A, Mazzocco C, Lepreux S, Decossas M,
Cubel G, Taras D, Blanc JF, Robinson DR, Rosenbaum J. Matrix
metalloproteinase 3 is present in the cell nucleus and is involved in
apoptosis. Am J Pathol 169: 1390 –1401, 2006.
118. Sohail A, Sun Q, Zhao H, Bernardo MM, Cho JA, Fridman R.
MT4-(MMP17) and MT6-MMP (MMP25), A unique set of membrane-
anchored matrix metalloproteinases: properties and expression in cancer.
Cancer Metastasis Rev 27: 289 –302, 2008.
119. Steinmann-Niggli K, Ziswiler R, Kung M, Marti HP. Inhibition of
Downloaded from http://ajprenal.physiology.org/ at University of South Dakota on November 18, 2012
matrix metalloproteinases attenuates anti-Thy1.1 nephritis. J Am Soc
Nephrol 9: 397–407, 1998.
120. Surendran K, Simon TC, Liapis H, McGuire JK. Matrilysin (MMP-7)
expression in renal tubular damage: association with Wnt4. Kidney Int
65: 2212–2222, 2004.
121. Sutton TA, Kelly KJ, Mang HE, Plotkin Z, Sandoval RM, Dagher
PC. Minocycline reduces renal microvascular leakage in a rat model of
ischemic renal injury. Am J Physiol Renal Physiol 288: F91–F97, 2005.
122. Swee M, Wilson CL, Wang Y, McGuire JK, Parks WC. Matrix
metalloproteinase-7 (matrilysin) controls neutrophil egress by generating
chemokine gradients. J Leukoc Biol 83: 1404 –1412, 2008.
123. Tan TK, Zheng G, Hsu TT, Wang Y, Lee VW, Tian X, Wang Y, Cao
Q, Wang Y, Harris DC. Macrophage matrix metalloproteinase-9 me-
diates epithelial-mesenchymal transition in vitro in murine renal tubular
cells. Am J Pathol 176: 1256 –1270, 2010.
124. Tarin C, Gomez M, Calvo E, Lopez JA, Zaragoza C. Endothelial
nitric oxide deficiency reduces MMP-13-mediated cleavage of ICAM-1
in vascular endothelium: a role in atherosclerosis. Arterioscler Thromb
Vasc Biol 29: 27–32, 2009.
125. Tashiro K, Koyanagi I, Ohara I, Ito T, Saitoh A, Horikoshi S,
Tomino Y. Levels of urinary matrix metalloproteinase-9 (MMP-9) and
renal injuries in patients with type 2 diabetic nephropathy. J Clin Lab
Anal 18: 206 –210, 2004.
126. Thrailkill KM, Clay Bunn R, Fowlkes JL. Matrix metalloproteinases:
their potential role in the pathogenesis of diabetic nephropathy. Endo-
crine 35: 1–10, 2009.
127. Thrailkill KM, Moreau CS, Cockrell GE, Jo CH, Bunn RC, Morales-
Pozzo AE, Lumpkin CK, Fowlkes JL. Disease and gender-specific
dysregulation of NGAL and MMP-9 in type 1 diabetes mellitus. Endo-
crine 37: 336 –343, 2010.
128. Tomita M, Koike H, Han GD, Shimizu F, Kawachi H. Decreased
collagen-degrading activity could be a marker of prolonged mesangial
matrix expansion. Clin Exp Nephrol 8: 17–26, 2004.
129. Tomlinson ML, Garcia-Morales C, Abu-Elmagd M, Wheeler GN.
Three matrix metalloproteinases are required in vivo for macrophage
migration during embryonic development. Mech Dev 125: 1059 –1070,
2008.
130. Tschesche H, Zolzer V, Triebel S, Bartsch S. The human neutrophil
lipocalin supports the allosteric activation of matrix metalloproteinases.
Eur J Biochem 268: 1918 –1928, 2001.
131. Turck J, Pollock AS, Lee LK, Marti HP, Lovett DH. Matrix metal-
loproteinase 2 (gelatinase A) regulates glomerular mesangial cell prolif-
eration and differentiation. J Biol Chem 271: 15074 –15083, 1996.
132. Tveita A, Rekvig OP, Zykova SN. Glomerular matrix metalloprotei-
nases and their regulators in the pathogenesis of lupus nephritis. Arthritis
Res Ther 10: 229, 2008.
133. Tveita AA, Rekvig OP, Zykova SN. Increased glomerular matrix
metalloproteinase activity in murine lupus nephritis. Kidney Int 74:
1150 –1158, 2008.
134. Urushihara M, Kagami S, Kuhara T, Tamaki T, Kuroda Y. Glomer-
ular distribution and gelatinolytic activity of matrix metalloproteinases in
human glomerulonephritis. Nephrol Dial Transplant 17: 1189 –1196,
2002.
135. van der Zijl NJ, Hanemaaijer R, Tushuizen ME, Schindhelm RK,
Boerop J, Rustemeijer C, Bilo HJ, Verheijen JH, Diamant M.
Urinary matrix metalloproteinase-8 and -9 activities in type 2 diabetic
subjects: A marker of incipient diabetic nephropathy? Clin Biochem 43:
635–639, 2010.
136. Van Lint P, Libert C. Matrix metalloproteinase-8: cleavage can be
decisive. Cytokine Growth Factor Rev 17: 217–223, 2006.

MMPs IN KIDNEY DISEASES
137. Van Wart HE, Birkedal-Hansen H. The cysteine switch: a principle of
regulation of metalloproteinase activity with potential applicability to the
entire matrix metalloproteinase gene family. Proc Natl Acad Sci USA 87:
5578 –5582, 1990.
138. Velasco G, Pendas AM, Fueyo A, Knauper V, Murphy G, Lopez-
Otin C. Cloning and characterization of human MMP-23, a new matrix
metalloproteinase predominantly expressed in reproductive tissues and
lacking conserved domains in other family members. J Biol Chem 274:
4570 –4576, 1999.
139. Visse R, Nagase H. Matrix metalloproteinases and tissue inhibitors of
metalloproteinases: structure, function, and biochemistry. Circ Res 92:
827–839, 2003.
140. Wang D, Dai C, Li Y, Liu Y. Canonical Wnt ␤-catenin signaling
mediates transforming growth factor-␤1-driven podocyte injury and
proteinuria. Kidney Int 80: 1159 –1169, 2011.
141. Wang X, Zhou Y, Tan R, Xiong M, He W, Fang L, Wen P, Jiang L,
Yang J. Mice lacking the matrix metalloproteinase-9 gene reduce renal
interstitial fibrosis in obstructive nephropathy. Am J Physiol Renal
Physiol 299: F973–F982, 2010.
142. Weisbord SD, Chen H, Stone RA, Kip KE, Fine MJ, Saul MI,
Palevsky PM. Associations of increases in serum creatinine with mor-
tality and length of hospital stay after coronary angiography. J Am Soc
Nephrol 17: 2871–2877, 2006.
143. Wickstrom SA, Alitalo K, Keski-Oja J. Endostatin signaling and
regulation of endothelial cell-matrix interactions. Adv Cancer Res 94:
197–229, 2005.
144. Williams JM, Zhang J, North P, Lacy S, Yakes M, Dahly-Vernon A,
Roman RJ. Evaluation of metalloprotease inhibitors on hypertension
and diabetic nephropathy. Am J Physiol Renal Physiol 300: F983–F998,
2011.
145. Wong W, DeVito J, Nguyen H, Sarracino D, Porcheray F, Dargon I,
Pelle PD, Collins AB, Tolkoff-Rubin N, Smith RN, Colvin R, Zorn E.
Chronic humoral rejection of human kidney allografts is associated with
MMP-2 accumulation in podocytes and its release in the urine. Am J
Transplant 10: 2463–2471, 2010.
AJP-Renal Physiol • doi:10.1152/ajprenal.00037.2012 • www.ajprenal.org
Review
F1361
146. Xu X, Jackson PL, Tanner S, Hardison MT, Abdul Roda M, Blalock
JE, Gaggar A. A self-propagating matrix metalloprotease-9 (MMP-9)
dependent cycle of chronic neutrophilic inflammation. PLoS One 6:
e15781, 2011.
147. Yamashita CM, Dolgonos L, Zemans RL, Young SK, Robertson J,
Briones N, Suzuki T, Campbell MN, Gauldie J, Radisky DC, Riches
DW, Yu G, Kaminski N, McCulloch CA, Downey GP. Matrix metal-
loproteinase 3 is a mediator of pulmonary fibrosis. Am J Pathol 179:
1733–1745, 2011.
148. 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: 1525–1538, 2002.
149. Yang MX, Qu X, Kong BH, Lam QL, Shao QQ, Deng BP, Ko KH,
Downloaded from http://ajprenal.physiology.org/ at University of South Dakota on November 18, 2012
Lu L. Membrane type 1-matrix metalloproteinase is involved in the
migration of human monocyte-derived dendritic cells. Immunol Cell Biol
84: 557–562, 2006.
150. Yao XM, Ye SD, Zai Z, Chen Y, Li XC, Yang GW, Wang YX, Chen
K. Simvastatin protects diabetic rats against kidney injury through the
suppression of renal matrix metalloproteinase-9 expression. J Endocrinol
Invest 33: 292–296, 2010.
151. Yen JH, Khayrullina T, Ganea D. PGE2-induced metalloproteinase-9
is essential for dendritic cell migration. Blood 111: 260 –270, 2008.
152. Zeisberg M, Duffield JS. Resolved: EMT produces fibroblasts in the
kidney. J Am Soc Nephrol 21: 1247–1253, 2010.
153. Zeisberg M, Khurana M, Rao VH, Cosgrove D, Rougier JP, Werner
MC, Shield CF 3rd, Werb Z, Kalluri R. Stage-specific action of matrix
metalloproteinases influences progressive hereditary kidney disease.
PLoS Med 3: e100, 2006.
154. Zheng G, Lyons JG, Tan TK, Wang Y, Hsu TT, Min D, Succar L,
Rangan GK, Hu M, Henderson BR, Alexander SI, Harris DC.
Disruption of E-cadherin by matrix metalloproteinase directly mediates
epithelial-mesenchymal transition downstream of transforming growth
factor-beta1 in renal tubular epithelial cells. Am J Pathol 175: 580 –591,
2009.