Néphrologie & Thérapeutique 12S (2016) S35–S38

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Progression and fibrosis

Molecular pathways of chronic kidney disease progression§

Frank Bienaimé a,b,c, Guillaume Canaud a,b,d, Khalil El Karoui a,b,c, Morgan Gallazzini a,b,
Fabiola Terzi a,b,*
a
Inserm U1151, Team mechanisms and therapeutic strategies of chronic kidney disease, Department ‘‘Growth and Signalling’’, Institut Necker–Enfants-
Malades, hôpital Necker–Enfants-Malades, 149, rue de Sèvres, 75015 Paris, France
b
Université Paris Descartes, 75015 Paris, France
c
Service d’explorations fonctionnelles, hôpital Necker–Enfants-Malades, 149, rue de Sèvres, 75015 Paris, France
d
Service de néphrologie–transplantation, hôpital Necker–Enfants-Malades, 149, rue de Sèvres, 75015 Paris, France

A R T I C L E I N F O A B S T R A C T

Keywords: Chronic kidney disease is characterized by the progressive loss of functional nephrons. This loss means
CKD that the remaining nephrons are put under stress and are forced to adapt in order to maintain kidney
Adaptation function. Over the time, the strains imposed by these adaptations result in a vicious circle in which the
Deterioration
loss of damaged nephrons results in the damage of the so far healthy nephrons. Hence, the rate of chronic
MTORC/AKT
kidney disease progression depends on the ability of the remaining nephrons to cope with stress. This
EGFR
ER stress article reviews the molecular pathways involved in the compensation and deterioration process after
LCN2 nephron reduction. In particular, we examine the role of mammalian target of rapamycin complex
(mTORC)/serine-threonine protein kinase AKT, epidermal growth factor receptor (EGFR) and unfolded
protein response pathways, as well as the pleiotropic function of Lipocalin 2. We also discuss the dual
role played by some of these pathways in acute and chronic kidney disease. Finally, the relevance of these
experimental finding to human chronic kidney disease is discussed.
ß 2016 Association Société de néphrologie. Publié par Elsevier Masson SAS. Tous droits réservés.

1. Introduction preventive strategies to slow down the rate of progression of

Chronic kidney disease is characterized by a progressive decline
in renal function to end stage renal disease that can occur
irrespective of the cause of the renal damage (diabetes, hyperten-
sion, ischemia or immune diseases), once a critical number of
nephrons has been lost. Chronic kidney disease represents a
worldwide concern: over 7 million people in the European
Community are affected by chronic renal failure and 300,000
are undergoing renal replacement therapy, either by dialysis or
transplantation. Grossly, 10% of the adult population is estimated
to suffer from chronic kidney disease [1]. These patients display an
increased risk factor for cardiovascular diseases and death.
Moreover, the quality of life of patients with chronic kidney
disease remains poor, due in large part to a complex set of
deleterious sequelae. Faced with the persistently poor outcome of
end stage renal disease, current clinical research efforts focus on
§
Article presented at the annual symposium ‘‘Actualités néphrologiques Jean-
Hamburger, hôpital Necker, 2016’’.
* Corresponding author at: Inserm U1151, Team mechanisms and therapeutic
strategies of chronic kidney disease, Tour Lavoisier 6e étage, 149, rue de Sèvres,
75015 Paris, France.
E-mail address: fabiola.terzi@inserm.fr (F. Terzi).
chronic kidney disease. Elucidating the molecular pathways
underlying the progression of chronic kidney disease is the first
step for the development of new therapeutic and pharmacological
targets and a key challenge for medical planning.
2. Mechanisms of chronic kidney disease progression:
importance of nephron loss
The mechanisms of chronic kidney disease progression remain
poorly understood. Attempts to dissect the molecular basis of
chronic kidney disease have been facilitated by the development of
several experimental models of renal deterioration. Among these,
the remnant kidney model is a mainstay, since nephron reduction
characterizes the evolution of most human chronic kidney disease.
Consequently, this model recapitulates many features of human
chronic kidney disease, including hypertension, proteinuria,
glomerular and tubulo-interstitial lesions. Over the last 50 years,
this model has led to the discovery of critical pathways and, more
importantly, to the design of therapeutic strategies to slow down
the progression of chronic kidney disease, such as the widely
clinically used renin-angiotensin inhibitors [2].
Experimental models of nephron reduction have shown that the
reduction in the number of functional nephrons triggers molecular

http://dx.doi.org/10.1016/j.nephro.2016.02.009
1769-7255/ß 2016 Association Société de néphrologie. Publié par Elsevier Masson SAS. Tous droits réservés.
S36 F. Bienaimé et al. / Néphrologie & Thérapeutique 12S (2016) S35–S38
and cellular events that promote compensatory growth of the
remaining ones to maintain kidney function [3]. However, over
time, the strain imposed by these adaptations results in mechani-
cal and metabolic stresses that lead to a vicious circle in which the
loss of the residual nephrons results in the damage of healthy
nephrons (overwork hypothesis) [3,4]. Hence, the rate of chronic
kidney disease progression crucially depends on the ability of
remaining nephrons to cope with stresses.
3. Role of haemodynamic adaptation
Since the pioneer works from Brenner et al., it has been known
that nephron reduction leads first to an adaptive response through
the increase of the blood flow and the intracapillary glomerular
pressure which end in higher single nephron glomerular filtration
rate [3]. The strain imposed by these adaptations results in
mechanical constraints of glomerular cells that ultimately lead to
glomerular damage, albuminuria and further nephron loss [5]. By
their position and function, podocytes are particularly exposed to
such mechanical stresses that try to counteract through a complex
regulation of their actin cytoskeleton. Based on these observations,
we hypothesized that, during nephron reduction, the fate of
podocytes might depend on their ability to engage an adaptive
genetic program to cope with the constraints imposed by the
increase in single nephron glomerular filtration rate. Among the
possible programs, we focused our attention on AKT kinases
because:
 these kinases deliver anti-apoptotic signals and mediate
cytoskeleton rearrangement [6–8];
 they appear to be positively regulated by the core proteins of the
slit diaphragm [9].
4. mTORC/AKT pathway: experimental proofs
AKT proteins are conserved cytosolic serine-threonine kinases
that regulate many cellular processes including survival, prolifer-
ation, migration and cytoskeleton organization [6]. In mammals,
three distinct genes encode AKT homologs: Akt1, Akt2 and Akt3,
respectively. AKT activation requires, first, its recruitment to
plasma membrane, which is initiated by phosphatidyl-inositol-3-
kinase (PI3K), then, the phosphorylation on Thr308 and Ser473 by
3-phosphoinositide-dependent protein kinase-1 (PDK1) and
mammalian target of rapamycin (mTOR) complex 2 (mTORC2),
respectively [8]. Once activated, AKT proteins phosphorylate
several substrates to regulate multiple cellular functions. Indirect
evidences suggest a role of AKT in podocyte physiology. In vitro,
AKT pathway inhibition reduces podocyte viability [10]. It has been
also shown that, in cultured podocytes, AKT can be activated by
nephrin, a protein that contributes to the slit diaphragm stability
[9]. Notably, nephrin is sought to transduce extracellular signals,
such as mechanical constraints, to the intracellular compartment
of the podocyte [10]. By applying different experimental models of
nephron reduction to genetically modified mice, we showed that
AKT2, but not AKT1, activation by mTORC2 plays an essential role
in podocyte cytoskeleton maintenance, survival and adaptation to
environmental constraints [11]. In fact, Akt2 gene deletion leads to
severe albuminuria and worsened glomerular lesions after
nephron reduction. Mechanistically, we observed that AKT2
triggers a compensatory program involving mouse double minute
2 (MDM2), glycogen synthase kinase 3 (GSK3) and ras-related C3
botulinum toxin substrate 1 (RAC1). Consistent with these
observations, previous studies have highlighted the important
function played by RAC1-GTP in the maintenance of podocytes
cytoskeleton organization and foot processes in mice and humans
[12,13]. It is worth noting that AKT2 mediates insulin signalling
and that the specific deletion of the insulin receptor in podocytes
mirrored the glomerular lesions observed during diabetic
nephropathy [14]. Hence, by integrating many messages ranging
from mechanical to metabolic stresses, AKT2 acts as a central node
of podocyte signaling.
5. mTORC/AKT pathway: from mice to humans
A major problem encountered in patients treated with
sirolimus, a mTORC inhibitor and one of the most widely used
immunosuppressive treatments, is its adverse effect on the kidney,
particularly in patients with compromised renal function. In fact,
several studies have reported that kidney transplant recipients
might develop proteinuria upon sirolimus treatment [15]. Our
translation studies have provided a rational basis to this
observation. In fact, we have demonstrated that, by preventing
the activation of AKT2 in kidney, sirolimus leads to marked
proteinuria and podocyte loss in transplanted recipients with
severe nephron reduction [11]. Interestingly, as in mice, mTORC2
rather mTORC1, seems to be involved in AKT activation and in the
deleterious effect of sirolimus. Sequential biopsies allowed us to
demonstrate that AKT activation may anticipate the toxicity of
sirolimus. Hence, in order to prevent to the adverse effects of
mTORC inhibitors, we suggest evaluating the state of AKT2
activation (phosphorylation) in all kidneys of patients suffering
from chronic kidney disease with compromised renal function.
6. Role of residual proteinuria
Convergent evidences from clinical and experimental studies
indicate that albuminuria and proteinuria are not simply markers
of chronic kidney disease progression, but active players in the
evolution of the disease [16]. Mechanistically, it has been proposed
that the proteins that escape into the glomerular filtrate have a
toxic effect on tubular cells and that, once damaged, tubular cells
lead to the development of interstitial fibrosis and inflammation
[17]. The increased production of endothelin-1, monocyte che-
moattractant protein 1 (MCP-1), RANTES (regulated upon activa-
tion normal T cell expressed and secreted), or complement
components have been involved in this toxic effect [17]. More
recently, a few studies have shown that the unfolded protein
response is also activated in tubular cells exposed to albumin [18–
20], but the pathophysiological role of such activation remains
unknown.
7. Endoplasmic reticulum stress/Lipocalin 2 pathway:
experimental proofs
The endoplasmic reticulum is a signalling platform that
responds to various cellular stresses by inducing a coordinated
response, the unfolded protein response [21]. During the unfolded
protein response, inositol-requiring enzyme 1a (IRE1a) promotes
the phosphorylation of c-JUN and the specific splicing of the
unfolded protein response transcription factor X-box binding
protein 1 (XBP1). Besides, protein kinase R (PKR)–like kinase
(PERK) phosphorylates eukaryotic translation-initiation factor 2a
(eIF2a): this reduces general translation but promotes translation
of activating transcription factor 4 (ATF4), which activates the
CCAAT/enhancer-binding protein homologous protein (CHOP). If
this adaptive response cannot overcome endoplasmic reticulum
stress, it triggers apoptotic cell death. Using experimental models
of proteinuric nephropathies, we have very recently uncovered a
novel endoplasmic reticulum stress pathway critically involved in
chronic kidney disease progression [22]. In fact, we observed that
 F. Bienaimé et al. / Néphrologie & Thérapeutique 12S (2016) S35–S38 S37

albuminuria stimulates, via a calcium release induced-endoplas- Among them, the epidermal growth factor receptor (EGFR)
mic reticulum stress, the overexpression of Lipocalin 2 (also known pathway is of particular interest.
as NGAL), a small-secreted iron transporting protein, in tubular
cells. Consistent with the role of Lipocalin 2 in chronic kidney
10. Epidermal growth factor receptor pathway
disease progression, Lcn2 gene inactivation decreases endoplasmic
reticulum stress-induced apoptosis and tubulo-interstitial lesions
The epidermal growth factor receptor (EGFR/HER1) belongs to a
and increases the survival rate in proteinuric mice [22]. Despite
receptor tyrosine kinases protein family that includes HER2/neu,
that several signalling pathways have been involved in the toxic
HER3, and HER4. EGFR can be activated by a family of closely
effect of proteinuria, none of them has led to the development of
related growth factors [27]. At least seven EGFR ligands, including
novel therapeutic strategies capable to slow down chronic kidney
transforming growth factor-a (TGF-a), epidermal growth factor
disease progression in humans. Unfolded protein response and
(EGF), heparin-binding EGF-like growth factor (HB-EGF), amphi-
endoplasmic reticulum stress can be targeted by various thera-
regulin, betacellulin, epigen and epiregualtin, have been identified
peutic compounds either Food and Drug Administration (FDA)-
in kidney cells [27]. Like other tyrosine kinase receptors, the EGFR
approved or in preclinical studies [23]. By using one of these
is directly activated by ligand binding which induces the activation
compounds, the 4-phenylbutyric acid (PBA), we were able to delay
of the intrinsic kinase domain and the subsequent phosphorylation
chronic kidney disease progression in proteinuric mice. The
of specific tyrosine residues. This phosphorylation triggers the
beneficial effect was observed despite the persistence of severe
activation of intracellular signalling pathways, including mitogen-
proteinuria, indicating that tubular cells are the target of PBA [22].
activated protein kinase (MAPK), signal transducer and activator of
transcription (STAT) and AKT pathways. The EGFR can be also
8. Endoplasmic reticulum stress/Lipocalin 2 pathway: from
transactivated by other signalling pathways [27]. We have
mice to humans
demonstrated that the activation of the EGFR, not only by its
direct ligands, but also by angiotensin II, a well-known mediator of
Urinary Lipocalin 2 excretion has been shown to be a biomarker
chronic kidney disease progression, accounts for the development
of chronic kidney disease progression, including in proteinuric
of renal lesions in several experimental models of chronic kidney
nephropathies [24]. In our study, we confirmed that Lipocalin 2
disease [28,29]. TGF-a, but not the EGF itself, mediates the cross-
was overexpressed in kidney biopsies of patients with different
talk between angiotensin II and EGF receptors [29]. Notably, the
types of proteinuric nephropathies [22]. Taking advantage of a
propensity to develop renal lesions after nephron reduction in
unique patient followed in our Nephrology department for a
specific mouse strains also involves the activation of EGFR through
lysinuric protein intolerance associated with proteinuria and
TGF-a [30–32]. The detrimental role of EGFR activation has been
treated by PBA, we showed that PBA administration decreases
confirmed in several experimental models of chronic kidney
urinary Lipocalin 2 excretion without affecting the severity of
disease, i.e. diabetes, hypertension, polycystic kidney diseases and
proteinuria [22]. Although this observation needs to be confirmed,
glomerulonephritis [33]. It has been also shown that albuminuria,
it suggests that:
aldosterone and endothelin 1 may lead to renal deterioration by
transactivating the EGFR in a ligand-depend manner [34,35],
 PBA might be valuable therapy for patients with proteinuirc
indicating that EGFR acts as a true signaling hub in the molecular
nephropathies;
networks leading to chronic kidney disease progression. Notably,
 urinary Lipocalin 2 excretion might be used to both identify
in several experimental models, the pharmacological inhibition of
patients that could benefit of the treatment and monitor its
EGFR has been shown to slow down the progression of chronic
efficacy.
kidney disease [30,33]. Several EGFR inhibitors have been
developed in cancers. Although they are not completely devoid
So far, the only available strategy to counteract the deleterious
of adverse effects, more targeted, and very likely less toxic
effect of proteinuria is the renin–angiotensin system inhibition,
therapeutic strategies are currently under development. For
which reduces the leakage of proteins from the glomerular
example, a blocking antibody directed against TGF-a has been
filtration barrier. However, a residual proteinuria is observed in
recently developed [36]. Our studies point to TGF-a as the critical
most patients under renin–angiotensin system blockade and the
ligand of the EGFR during chronic kidney disease progression.
nephroprotective effect of renin–angiotensin system inhibitors
Interestingly, the administration of this antibody to mice with
may decline over time. Hence, our study provides the rational for
diabetes nephropathy decreases the rate of chronic kidney disease
the development of a multitarget therapy for proteinuric chronic
progression. It has to be mentioned that a phase 2 study is ongoing
kidney disease patients, susceptible to inhibit not only proteinuria
in the USA to evaluate the potential of this anti-TGF-a antibody in
leakage, but also its tubular toxicity.
patients with diabetic nephropathy.
9. Role of compensatory growth
11. Dual role of signalling pathways in acute and chronic
As indicated above, not only hemodynamic adaptations, but kidney disease
also the compensatory growth has been involved in the deteriora-
tion of remaining nephrons after nephron reduction [3]. The A striking observation in kidney physiopathology is the
identity of the molecular networks at the origin of the initial apparent opposite effect of the activation of some signalling
compensatory processes and the signaling leading to the subse- pathways in the outcome of acute versus chronic kidney disease.
quent appearance of lesions have been only partially elucidated. It For example, it has been observed that EGFR-driven proliferation
has been suggested that growth factors play a key role. Indeed: may either improve regeneration after an acute kidney injury, or,
paradoxically, accelerate lesion development during a chronic
 their expression increases in many nephropathies characterized injury [33,37]. Similarly, we have previously shown that
by intense cell proliferation; Lipocalin 2 favours the development of renal lesions after nephron
 their inhibition prevents renal deterioration; reduction by mediating the mitogenic effect of EGFR [38]. However,
 the overexpression of several of them leads to lesion develop- Lipocalin 2 has been also shown to be involved in the regenerative
ment in transgenic mice [25,26]. proliferation that follows an ischemic injury [39]. The cellular
S38 F. Bienaimé et al. / Néphrologie & Thérapeutique 12S (2016) S35–S38
events and genetic networks that enable chronic injury to distort
the regenerative response of EGFR or Lipocalin 2 into a detrimental
process are unknown. We demonstrated that the selective
inhibition of EGFR in tubular cells prevents both tubular cell
proliferation and interstitial fibrosis, suggesting that proliferating
cells might secrete paracrine profibrotic mediators involved in the
cross-talk between tubular and interstitial cells [28]. Consistently,
it has been shown that a cell cycle G2/M arrest in proliferating
tubular cells may trigger profibrotic gene expression in experi-
mental chronic kidney disease models [40]. On the other hand, we
have shown that the distortion of the mitotic spindle orientation in
proliferating cell results in tubular dilations after an acute injury,
suggesting that the nature of tubular cell proliferation might differ
with respect to planar cell polarity properties of tubular epithelia
[41]. Whether EGFR trigger specific downstream signalling
pathways in acute and chronic kidney disease to modulate these
events is an interesting hypothesis that deserve to be studied.
12. Conclusions
Experimental studies have identified novel signalling path-
ways critically involved in both renal compensation and
deterioration. The elucidation of these pathways has led to the
identification of potential valuable biomarkers capable to predict
the evolution of the disease or the improved use of some drugs. In
addition, they have uncovered novel potential therapeutic
targets. More importantly, translation studies have demonstrated
that these pathways are relevant to human chronic kidney
disease. Although further studies are required to better charac-
terized their role and identify the critical intermediates, this is the
proof that experimental models of nephron reduction are a
precious tool for elucidating the pathophysiology of chronic
kidney disease progression.
Disclosure of interest
The authors declare that they have no competing interest.
References
[1] Zhang QL, Rothenbacher D. Prevalence of chronic kidney disease in popula-
tion-based studies: systematic review. BMC Public Health 2008;8:117–27.
[2] Remuzzi G, Benigni A, Remuzz A. Mechanisms of progression and regression
of renal lesions of chronic nephropathies and diabetes. J Clin Invest
2006;116:288–96.
[3] Hostetter TH. Progression of renal disease and renal hypertrophy. Annu Rev
Physiol 1995;57:263–78.
[4] Kriz W, LeHir M. Pathways to nephron loss starting from glomerular diseases-
insights from animal models. Kidney Int 2005;67:404–19.
[5] Kriz W, Lemely KV. A potential role for mechanical forces in the detachement
of podocytes and the proresision of CKD. Am J Soc Nephrol 2015;26:258–69.
[6] Franke TF. Intracellular signaling by Akt: bound to be specific. Sci Signal 1
2008;1(24):pe29.
[7] Ceci M, Ross J, Condorelli G. Molecular determinants of the physiological
adaptation to stress in the cardiomyocyte: a focus on AKT. J Mol Cell Cardiol
2004;37:905–12.
[8] Manning BD, Cantley LC. AKT/PKB signaling: navigating downstream. Cell
2007;129:1261–74.
[9] Huber TB, Hartleben B, Kim J, Schmidts M, Schermer B, Keil A, et al. Nephrin
and CD2AP associate with phosphoinositide 3-OH kinase and stimulate AKT-
dependent signaling. Mol Cell Biol 2003;23:4917–28.
[10] Chuang PY, He JC. Signaling in regulation of podocyte phenotypes. Nephron
Physiol 2009;111:9–15.
[11] Canaud G, Bienaimé F, Viau A, Treins C, Baron W, Nguyen C, et al. AKT2 is
essential to maintain podocyte viability and function during chronic kidney
disease. Nat Med 2013;19:1288–96.
[12] Shibata S, Nagase M, Yoshida S, Kawarazaki W, Kurihara H, Tanaka H, et al.
Modification of mineralocorticoid receptor function by Rac1-GTPase: impli-
cation in proteinuric kidney disease. Nat Med 2008;14:1370–6.
[13] Akilesh S, Suleiman H, Yu H, Stander MC, Lavin P, Gbadegesin R, et al. Arhgap24
inactivates Rac1 in mouse podocytes, and a mutant form is associated with
familial focal segmental glomerulosclerosis. J Clin Invest 2011;121:4127–37.
[14] Welsh GI, Hale LJ, Eremina V, Jeansson M, Maezawa Y, Lennon R, et al. Insulin
signaling to the glomerular podocyte is critical for normal kidney function. Cell
Metab 2010;12:329–40.
[15] Letavernier E, Bruneval P, Vandermeersch S, Perez J, Mandet C, Belair MF, et al.
Sirolimus interacts with pathways essential for podocyte integrity. Nephrol
Dial Transplant 2009;24:630–8.
[16] Cravedi P, Ruggenenti P, Remuzzi G. Proteinuria should be used as a surrogate
in CKD. Nat Rev Nephrol 2012;8:301–6.
[17] Ruggenenti P, Cravedi P, Remuzzi G. Mechanisms and treatment of CKD. J Am
Soc Nephrol 2012;23:1917–28.
[18] Ohse T, Inagi R, Tanaka T, Ota T, Miyata T, Kojima I, et al. Albumin induces
endoplasmic reticulum stress and apoptosis in renal proximal tubular cells.
Kidney Int 2006;70:1447–55.
[19] Lindenmeyer MT, Rastaldi MP, Ikehata M, Neusser MA, Kretzler M, Cohen CD,
et al. Proteinuria and hyperglycemia induce endoplasmic reticulum stress. J
Am Soc Nephrol 2008;19:2225–36.
[20] Wu X, He Y, Jing Y, Li K, Zhang J. Albumin overload induces apoptosis in renal
tubular epithelial cells through a CHOP-dependent pathway. OMICS
2010;14:61–73.
[21] Walter P, Ron D. The unfolded protein response: from stress pathway to
homeostatic regulation. Science 2011;334:1081–6.
[22] El Karoui K, Viau A, Dellis O, Bagattin A, Nguyen C, Baron W, et al. Endoplasmic
reticulum stress drives proteinuria-induced kidney lesions via Lipocalin 2. Nat
Commun 2016;7:10330.
[23] Hetz C, Chevet E, Harding HP. Targeting the unfolded protein response in
disease. Nat Rev Drug Discov 2013;12:703–19.
[24] Bolignano D, Coppolino G, Campo S, Aloisi C, Nicocia G, Frisina N, et al. Urinary
neutrophil gelatinase-associated lipocalin (NGAL) is associated with severity
of renal disease in proteinuric patients. Nephrol Dial Transplant 2008;23:
414–6.
[25] Kok HM, Falke LL, Goldschmeding R, Nguyen TQ. Targeting CTGF, EGF and
PDGF pathways to prevent progression of kidney disease. Nat Rev Nephrol
2014;10:700–11.
[26] Bottinger EP. TGF-beta in renal injury disease. Semin Nephrol 2007;27:309–
20.
[27] Wilson KJ, Gilmore JL, Foley MA, David J, Riese II. Functional selectivity of EGF
family peptide growth factors: implications for cancer. Pharmacol Ther
2009;122:1–8.
[28] Terzi F, Burtin M, Hekmati M, Federici P, Grimber G, Briand P, et al. Targeted
expression of a dominant-negative EGFR in the kidney reduces tubulo-inter-
stitial lesions after renal injury. J Clin Invest 2000;106:225–34.
[29] Lautrette A, Li S, Alili R, Sunnarborg SW, Burtin M, Lee DC, et al. Angiotensin II
and EGF receptor cross-talk in chronic kidney diseases: a new therapeutic
approach. Nat Med 2005;11:867–74.
[30] Laouari D, Burtin M, Phelep A, Martino C, Pillebout E, Montagutelli X, et al. TGF-
alpha mediates genetic susceptibility to chronic kidney disease. J Am Soc
Nephrol 2011;22:327–35.
[31] Laouari D, Burtin M, Phelep A, Bienaimé F, Noël LH, Lee DC, et al. A transcrip-
tional network underlies susceptibility to kidney disease progression. EMBO
Mol Med 2012;4:825–39.
[32] Pillebout E, Weitzman JB, Burtin M, Martino C, Federici P, Yaniv M, et al. JunD
protects against chronic kidney disease by regulating paracrine mitogens. J
Clin Invest 2003;112:843–52.
[33] Zeng F, Singh AB, Harris RC. The role of the EGF family of ligands and receptors
in renal development, physiology and pathophysiology. Exp Cell Res
2009;315:602–10.
[34] Grossmann C, Gekle M. Non-classical actions of the mineralocorticoid recep-
tor: misuse of EGF receptors? Mol Cell Endicronol 2007;277:6–12.
[35] Buelli S, Rosano L, Gagliardini E, Corna D, Longaretti L, Pezzota A, et al. b-
arrestin-1 drives endothelin-1-mediated podocyte activation and sustains
renal injury. J Am Soc Nephrol 2014;25:523–33.
[36] Beidler CB, Petrovan RJ, Conner EM, Boyles JS, Yang DD, Harlan SM, et al.
Generation and activity of a humanized monoclonal antibody that selectively
neutralizes the epidermal growth factor receptor ligands transforming growth
factor-a and epiregulin. J Pharmacol Exp Ther 2014;349:330–43.
[37] Humes HD, Cieslinski DA, Coimbra TM, Messana JM, Galvao C. Epidermal
growth factor enhances tubular cell regeneration and repair and accelerates
the recovery of renal function in postischemic acute renal failure. J Clin Invest
1989;84:1757–61.
[38] Viau A, El Karoui K, Laouari D, Burtin M, Nguyen C, Mori K, et al. Lipocalin 2 is
essential for chronic kidney disease progression in mice and humans. J Clin
Invest 2010;120:4065–76.
[39] Mori K, Lee HT, Rapoport D, Drexler IR, Foster K, Yang J, et al. Endocytic delivery
of lipocalin–siderophore–iron complex rescues the kidney from ischemia-
reperfusion injury. J Clin Invest 2005;115:610–21.
[40] Yang L, Besschetnova TY, Brooks CR, Shah JV, Bonventre JV. Epithelial cell cycle
arrest in G2/M mediates kidney fibrosis after injury. Nat Med 2010;16:535–43.
[41] Verdeguer F, Le Corre S, Fischer E, Callens C, Garbay S, Doyen A, et al. A mitotic
transcriptional switch in polycystic kidney disease. Nat Med 2010;16:106–10.