Transcriptional regulators in kidney disease: gatekeepers of ...
TIGS-649; No of Pages 11
Transcriptional regulators in kidney
disease: gatekeepers of renal
N. Henriette Uhlenhaut and Mathias Treier
Developmental Biology Unit, European Molecular Biology Laboratory, 69117 Heidelberg, Germany
Although we are rapidly gaining a more complete associated with the development of glomerulosclerosis
understanding of the genes required for kidney function, or interstitial ﬁbrosis that result from the reversal of
the molecular pathways that actively maintain organ developmental processes that were originally used to build
homeostasis are only beginning to emerge. The study the kidney. Therefore, some of the pathophysiological
of the most common genetic cause of renal failure,
polycystic kidney disease, has revealed a surprising role
for primary cilia in controlling nuclear gene expression Glossary
and cell division during development as well as main- Anosmia: absence of the ability to smell.
tenance of kidney architecture. Conditions that disturb Autosomal dominant polycystic kidney disease (ADPKD): hereditary disorder
characterized by the presence of multiple fluid-filled cysts inside enlarged kidneys;
kidney integrity seem to be associated with reversal of cysts arise from all nephron segments.
developmental processes that ultimately lead to kidney Autosomal recessive polycystic kidney disease (ARPKD): recessively inherited
disease similar to ADPKD, but cysts derive primarily from dilation of the collecting
ﬁbrosis and end-stage renal disease (ESRD). In this
review, we discuss transcriptional regulators and net- Bardet-Biedl syndrome (BBS): human genetic disorder including kidney abnorm-
works that are important in kidney disease, focusing alities, retinal degeneration, mental retardation, obesity, diabetes, polydactyly and
on those that mediate cilia function and drive renal Chronic kidney disease (CKD): progressive decline of kidney function, leading to
ﬁbrosis. kidney failure.
Collecting duct: epithelial tubes derived from the branched ureteric bud, draining
Chronic kidney disease: an emerging pandemic health the urine from the nephrons into the renal papilla.
End-stage renal disease (ESRD): kidney failure (the need for dialysis).
problem Epithelial-to-mesenchymal transition (EMT): process during which epithelial cells
Our kidneys serve important physiological functions to acquire mesenchymal, fibroblast-like properties (with reduced intercellular adhe-
sion and increased motility); the reverse process is called mesenchymal-to-
excrete waste products from the body and balance the body
epithelial transition (MET).
ﬂuids. Disturbance in the renal ﬁltration process can pose a Fibrosis: formation of scar (fibrous) tissue.
serious health threat. Currently, 10% of the global adult Glomerulosclerosis: scarring of the glomerulus, which impairs the filtration
process; often observed in chronic kidney disease.
population, regardless of ethnic origin, are affected by Glomerulus: a small group of looping blood vessels surrounded by Bowman’s
chronic kidney disease. An estimated 1.5 million patients capsule where the blood is filtered and urine is formed; consists of podocytes,
are dependent on renal replacement therapy [1,2]. endothelial and mesangial cells; see Figure I.
Lymphedema-Distichiasis syndrome: a condition that affects the function of the
For many years, the kidney has been a classical model lymphatic system resulting in extra eyelashes and tissue swelling.
for studying organogenesis (see Boxes 1 and 2 for a brief Mesangial cells: supportive cells within the glomerulus.
overview). Research on human genetic disorders associ- Metanephric mesenchyme (MM): an aggregate of mesenchymal cells in the
embryo from which renal stroma and nephrons originate.
ated with renal malfunction, in conjunction with the Nephron: the basic functional unit of the kidney, consisting of glomerulus,
analysis of gene disruption studies in mice and other model proximal tubule, loop of Henle, distal tubule, and collecting duct.
organisms, has led to the identiﬁcation of many transcrip- Nephronophthisis (NPHP): autosomal recessive disorder affecting juveniles;
progressive deterioration of kidney function, with medullary cysts, tubular
tion factors required for kidney development and homeo- degeneration and fibrosis. Phthisis (Greek) = a dwindling or wasting away.
stasis (Box 2). Despite the wealth of information available, Nephropathy: kidney disease.
we are still far from an integrative picture of the regulatory Podocyte: epithelial cells in the glomerulus that form part of the filtration barrier.
Polyuria: excessive excretion of urine.
networks that maintain the integrity of the mature kidney. Proteinuria: protein in the urine, a sign of renal dysfunction.
Modulation of signaling pathway strength by extrinsic Renal agenesis: absence of kidneys caused by a developmental defect.
Renal dysplasia: abnormal development of the kidneys (with regard to size and
factors results in gene expression program changes that
precede the observed morphological alterations in chronic Renal replacement therapy: life-supporting treatments for renal failure, such as
kidney disease. Thus, understanding the transcriptional dialysis and kidney transplantation.
Renal tubule: the elongated, tube-like part of the nephron, made up of the promixal
networks that maintain cell type identity in the mature and distal convoluted tubules and the loop of Henle.
kidney provides a promising entry point for future thera- Situs inversus: a condition in which the inner organs are arranged in a perfect
peutic interventions . Many forms of chronic kidney mirror image reversal of the normal positioning
Slit diaphragm: transmembrane structure between podocyte foot processes
disease (i.e. diabetic nephropathy, nephronophthisis) are creating a sieve.
Ureteric bud: epithelial protrusion (outpouching) from the Wolffian/nephric duct
that invades the metanephric mesenchyme during kidney development and gives
rise to the collecting duct system.
Corresponding author: Treier, M. (firstname.lastname@example.org).
0168-9525/$ – see front matter ß 2008 Elsevier Ltd. All rights reserved. doi:10.1016/j.tig.2008.05.001 Available online xxxxxx 1
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Table 1. Transcription factors associated with human renal disease
Gene Murine kidney phenotype Human syndrome OMIM
EYA1 Agenesis, no metanephric mesenchyme speciﬁed Bbranchio-otorenal syndrome: hearing loss, ear pits, branchial cysts 601653
or ﬁstulas, kidney anomalies a
FOXC1 Positioning of ureteric bud affected Axenfeld-Rieger syndrome (congenital ocular disorder) and 601090
congenital anomalies of the kidney and urinary tract a
FOXC2 Kidney hypoplasia, glomerular defects, ureteric bud Lymphedema-Distichiasis syndrome with renal disease and diabetes 602402
positioning affected mellitus a
GATA3 No ureteric branching, no metanephric differentiation HDR syndrome: hypoparathyroidism, sensorineural deafness and 131320
renal disease a
GLI3 Expression of a truncated instead of full-length Gli3 Pallister-Hall syndrome: ﬁngers and toes affected, benign 165240
protein mimics Pallister-Hall syndrome; kidney hypothalamic tumors, associated with renal anomalies (and others) a
development is abnormal
GLIS2 Kidney degeneration and cysts Nephronophthisis 608539
GLIS3 Polycystic kidneys Diabetes mellitus, hypothyroidism and polycystic kidneys 610192
HNF1b Cystic kidneys Renal cysts and diabetes syndrome 189907
LMX1b Impaired podocyte differentiation Nail Patella syndrome, including nephropathy a 602575
NFIA Ureteral and renal defects Central nervous system malformations and urinary tract defects a 600727
PAX2 Agenesis, nephric duct is not maintained Renal-Coloboma syndrome: optic nerve abnormalities, 167409
vesicoureteral reﬂux and renal hypoplasia a
SALL1 Agenesis, no ureteric bud outgrowth Townes-Brocks syndrome: abnormalities in thumbs, feet, heart, ears 602218
(impaired hearing), kidney; imperforate anus a
SALL4 Renal hypoplasia (agenesis in Sall1/Sall 4 compound Duane-Radial Ray (or Okihiro) syndrome associated with kidney 607343
heterozygotes) defects a
SIX1 No ureteric bud invasion, metanephric mesenchyme Branchio-otorenal) syndrome a 601205
is not sustained
SIX5 Unknown Branchio-otorenal) syndrome a 600963
WT1 No kidneys Wilm’s tumor, Wilm’s tumor-aniridia-genitourinary anomalies- 607102
mental retardation syndrome, Denys-Drash syndrome, Frasier
syndrome, diffuse mesangial sclerosis a
In humans, many of these syndromes are caused by haploinsufﬁciency, whereas the phenotype of many mouse mutants only manifests itself in the homozygous situation.
processes observed in chronic kidney disease are better proteins has led to the unifying theory that polycystic kidney
understood in light of normal kidney development. Sur- diseases are associated with a defect in primary cilia func-
prisingly, many transcriptional regulators that when tion [5,6].
mutated cause congenital abnormalities of the kidney, such Nearly all nondividing cells of the body extend a single
as renal agenesis, renal hypoplasia, dysplasia or uretic primary, nonmotile cilium into the extracellular space.
malformations, are reactivated during chronic kidney dis- Primary cilia are sensory organelles involved in photore-
eases (summarized in Table 1 and Box 2; for a review, see ception, olfaction and mechanosensation. They consist of a
Ref. ). central axoneme built of microtubules, covered by a
Here we focus on emerging evidence that suggests that specialized plasma membrane. Ciliary function depends
developmental gene expression programs are reactivated on intraﬂagellar transport (IFT) along their microtubules,
in chronic renal disease, pointing toward an underappre- because there is no protein synthesis within the cilium
ciated cellular plasticity of renal cells. Furthermore, we itself [7,8] (Figure 1).
discuss recent ﬁndings that localization and processing of The membrane proteins encoded by PKD1, PKD2 and
transcriptional regulators at the cilium are crucial for the PKHD1 as well as the NPHP and Bardet-Biedl-syndrome
maintenance of kidney homeostasis. (BBS) proteins localize to primary cilia and/or basal bodies
or centrosomes. Consequently, mislocalisation of these
Cystic kidney diseases are ciliopathies proteins caused by absence of renal cilia or disruption of
Cystic renal diseases are the most common genetic cause of cilia function causes cyst formation . Elegant genetic
end-stage renal disease (ESRD) . Among children, experiments in adult mice using a tamoxifen-inducible Cre
nephronophthisis (NPHP) and autosomal recessive polycys- recombinase system have shown that loss of cilia through
tic kidney disease (ARPKD) are predominant, whereas disruption of IFT leads to slow onset cystic kidney disease
autosomal dominant polycystic kidney disease (ADPKD) . A similarly designed study that induced PKD1 inacti-
prevails among adults. Mutations in the polycystin-1 vation in the mature kidney reported the same ﬁndings
(PKD1) and polycystin-2 (PKD2) genes are responsible for . Although the progression of the disease phenotype in
most ADPKD cases, whereas PKHD1 mutations account both cases was less aggressive than that observed after
predominantly for ARPKD. The major steps of early kidney disruption of IFT or PKD1 during development, these
development proceed normally in patients with polycystic results nevertheless suggest that cilia function is required
kidney disease, but terminal differentiation (i.e. the epi- to actively maintain kidney architecture throughout life.
thelial morphology of renal cells) cannot be sustained, In addition to polycystic kidney disease, people with
resulting in the functional tubular architecture being dis- cilia-associated genetic disorders often present with
rupted by ﬂuid-ﬁlled cysts. Several genes responsible for retinal degeneration, liver cysts and ﬁbrosis, anosmia,
cyst development have been identiﬁed by positional cloning situs inversus and systemic phenotypes such as obesity,
in human patients, and the subsequent study of these diabetes, heart defects, hypertension, as well as skeletal
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and neurological defects . Dysfunction of motile cilia These studies have illuminated the molecular mechanisms
such as the sperm’s ﬂagellum or the ones lining our air- downstream of Hh signaling in kidney development and
ways and fallopian tubes can lead to laterality defects, can explain the malformations found in Pallister-Hall
respiratory problems, infertility and hydrocephalus . syndrome that are thought to be caused by expression of
a dominant-negative GLI3 repressor.
The function of the cilium in hedgehog signaling The dependence of Hh signaling on ciliary localization
Mouse genetic data have provided compelling evidence leads to the question as to how the signal is transmitted
that apart from their role as sensory organelles, cilia are from the cilium to the nucleus. In a surprising twist to the
essential for Hedgehog (Hh) signal transduction. Mam- Hh story, Patched and Gli transcription factors were found
malian Hh signaling is mediated by three Gli-Kruppel to localize in the cilium, and Smoothened was shown to
transcription factor family members (Gli1–3). Without a move into the cilium in response to the Hh ligand, resulting
Hh signal, Patched (the Hedgehog receptor) inhibits in processing of the Gli transcription factors within the
Smoothened, and the Gli transcription factors are cleaved cilium. Consequently, defects in IFT, or other ciliary func-
to repressor forms, whereas presence of a Hh signal tions, can lead to disruption of Hh signaling [13,16].
relieves this inhibition, resulting in full-length Gli
proteins entering the nucleus and serving as transcrip- Glis factors: novel players in renal disease
tional activators (reviewed in Refs. [12,13]). Evidence for a Further clues as to how signaling within and from the
role of Sonic hedgehog (Shh) in kidney function has come primary cilium funnels into nuclear gene expression to
from the analysis of human patients with renal malfor- maintain polarity of renal epithelial cells in the mature
mations associated with Pallister-Hall syndrome kidney are now emerging. Recent evidence suggests that
(Table 1), which is caused by mutations in the GLI3 gene. loss of function mutations in the murine zinc ﬁnger tran-
These mutations are thought to result in a truncated GLI3 scription factor Gli-similar 2 (Glis2), as well as in human
protein, and mice expressing only this shortened form GLIS2, lead to nephronophthisis [17,18]. Glis2 is one of
have defective kidney development [12,14]. three Glis transcription factor family members whose zinc
Mice with homozygous mutations for Shh or those ﬁngers share high homology with the Gli family. Like the
treated with cyclopamine (a Hedgehog antagonist), show Gli proteins, Glis2 is detected in the primary cilium, but it
severe disruption of renal organogenesis, in the worst cases is not required for proper cilia formation. Interestingly,
resulting in a complete lack of kidneys. In the absence of Glis2 seems to act as a transcriptional repressor by binding
Hh signaling, reduced expression of Pax2, Sall1, cell cycle to Gli-consensus DNA binding sites and suppressing devel-
regulators (CyclinD1 and N-Myc), Gli1 and Gli2 was opmental gene expression programs once kidney architec-
observed. Intriguingly, Gli3 expression was increased in ture is established. Notably, all three Glis family members
the absence of Shh, and deletion of Gli3 rescued the renal are expressed in overlapping patterns in the adult mouse
phenotype of ShhÀ/À mice, restoring expression of Pax2, kidney. Furthermore, mutations in GLIS3 have been
Sall1, CyclinD1, N-Myc, Gli1 and Gli2 . These results shown to cause polycystic kidneys in humans  and
together strongly suggest that these genes are direct tar- mice (Uhlenhaut and Treier, unpublished observations).
gets of the Gli transcription factors, whereby Gli1 and 2 act Thus, Glis proteins in the adult kidney might be part of a
as transcriptional activators and Gli3 predominantly func- transcriptional network downstream of cilia signaling
tions as a transcriptional repressor in the absence of Shh. required for kidney integrity. It will be important to deter-
Box 1. An overview of kidney development
Mammalian kidney development proceeds through three successive until they finally connect with the collecting duct. This system of
steps, termed the pronephros, the mesonephros and the metane- branching and differentiation is reiterated until nephrogenesis is
phros. The pronephros is formed first and most rostrally (at E8.5 in completed shortly after birth in mice (reviewed in Refs. [74,75]).
the mouse), followed by a more caudal formation of the mesonephros A mature nephron consists of highly specialized cell types carrying
and finally the metanephros (at E10.5). The first two are transient out various physiological functions associated with waste excretion
structures in mammals, and only the metanephros will become the from the blood. One end of the nephron is formed by the glomerulus,
definite adult kidney [74,75] (see Figure I). followed by the proximal convoluted tubule, Henle’s loop and the
Kidney development is characterized by sequential reciprocal distal convoluted tubule, which inserts into the collecting duct. The
inductive interactions and mesenchymal-to-epithelial transforma- initial filtration of the blood occurs inside the glomerulus, where
tions. It is initiated with the formation of the nephric ducts, or fenestrated endothelial capillary cells and glomerular podocytes
Wolffian ducts (at E8 in the mouse), two epithelial tubes that originate create a filter (reviewed in Ref. ). This initial filtrate is concentrated
from the intermediate mesoderm and extend toward the posterior of by selective reabsorption along the different segments of the renal
the embryo. Metanephros development depends on interactions tubule. Glucose, amino acids, electrolytes and peptides are reab-
between the metanephric mesenchyme (MM), a specialized group sorbed in the proximal convoluted tubule, whereas water and
of kidney precursor cells, and the nephric duct. At the level of the electrolytes are taken up by Henle’s loop and the distal convoluted
hindlimb bud, signaling from the MM induces evagination of the tubule, because of the segmental expression of distinct sets of solute
ureteric bud (UB) from the nephric duct, which will invade the MM transporters . Defects in the podocyte foot processes enveloping
and form multiple branches. These branches will later form the the glomerular capillaries or in the basement membrane between the
collecting duct system that funnels the urine into the bladder. At the two cell types usually lead to protein loss into the urine (proteinuria).
tips of the branching ureter, the surrounding mesenchyme is induced Accordingly, malfunction of the above mentioned tubular segments
to condense, epithelialize and differentiate into mature nephrons. The generally results in abnormally high levels of the corresponding
differentiation of nephrons occurs through morphogenetic stages that molecules (e.g. glucose or electrolytes) within the urine, polyuria and
are referred to as renal vesicles and comma- and S-shaped bodies dehydration.
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Figure I. Schematic overview of mammalian kidney development and morphology. Kidney development proceeds through three stages: pronephros, mesonephros and
metanephros. (a) The metanephros becomes the permanent kidney and is formed by invasion and branching of the ureteric bud from the nephric duct into the
metanephric mesenchyme in a process of reciprocal inductive interactions. (b) The ureteric branches give rise to the collecting duct system and induce epithelialization
of the surrounding mesenchyme, first creating renal vesicles and then comma- and S-shaped bodies and finally nephrons that join the collecting duct. (c) The nephron
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Box 2. Transcription factors in early kidney development
The transcriptional networks governing early kidney development have Gndf and Six2 , so these genes are all part of a common pathway
been reviewed extensively elsewhere [4,74–76]. To summarize briefly, regulating early kidney development. Lineage specification events
many of the early specification events center around the activation of require the establishment of gene expression patterns that is most
glial cell line-derived neurotrophic factor (GDNF), a crucial signaling likely achieved through epigenetic modifications of local chromatin
molecule that is secreted by the metanephric mesenchyme (MM) to structures. Pax2 has been reported to recruit the assembly of a histone
induce budding and branching of the ureter. GDNF signals through its H3 lysine 4 methyltransferase complex through interaction with Pax
receptor tyrosine kinase Ret and its coreceptor Gfra1, both of which are transcription activating domain interacting protein (PTIP) to activate
expressed in the nephric duct . target promoters , which might be a hint at a general mechanism of
The evolutionarily conserved transcriptional hierarchy or circuitry of cell fate determination via this regulatory network.
Eya/Pax/Six protein families are fundamental regulators of early kidney Apart from the regulation of Gdnf/Ret expression, other pathways
development . Mutations in human EYA1, SIX1 and SIX5 genes parallel to the aforementioned Eya1 and Pax2/8 are required for proper
have been shown to underlie the branchial arch defects, hearing loss induction and specification of the metanephric field along the
and renal anomalies associated with BOR (branchio-oto-renal) syn- rostrocaudal axis. Early kidney development also requires expression
drome [78,79] (see Table 1). Pax2 and Pax8 cooperate in nephric lineage of Odd1 and Lim1 , two transcription factors expressed in the
specification. Mice homozygous mutant for the Pax2 gene alone fail to intermediate mesoderm. Interestingly, the zinc-finger transcription
induce the metanephric kidney, and Pax2/Pax8 double mutant mice fail factor Odd1 is downregulated on tubule differentiation, and persistent
to form the pronephros. Likewise, in Eya1 homozygous mutant mice, expression of Odd1 in the chick prevents differentiation .
the metanephric mesenchyme fails to be specified, which results in Other genes required for renal branching morphogenesis include
renal agenesis. Sall1 and Sall4, zinc finger proteins homologous to the Drosophila
In the absence of the homeobox transcription factor Six1, which is gene spalt , the homeobox factor Emx2, which is required for
expressed in the uninduced metanephric mesenchyme, ureteric bud ureteric bud functions after Pax2 , and WT1. WT1 mutations
invasion is abolished, and the MM subsequently undergoes apoptosis underlie the urogenital malformations in WAGR, Denys-Drash, Frasier
. Similar to the observed synergy between Pax2 and Pax8, Six1/Six4 syndromes and Wilm’s tumor (reviewed in Ref. ).
double mutants display a complete loss of a Pax2-expressing The reciprocal inductive interactions between the ureteric bud (UB)
metanephric mesenchyme . Six2 homozygous mutant mice have and the MM suggest the involvement of secreted signaling molecules
a unique phenotype of kidney hypoplasia that is caused by early on top of GDNF. One important player that has surfaced in this process
depletion of the mesenchymal precursor pool and premature differ- is the canonical Wnt pathway: Analysis of mutant mice has divulged
entiation of the mesenchyme into nephrons, which also results in fewer that Wnt9b is a primary signal necessary for renal vesicle induction,
ureteric branches . including Wnt4 production . Wnt4 itself seems to be an autocrine
Not surprisingly, the Hox11 cluster, which is crucial for embryonic factor necessary for differentiation of the MM into epithelial nephrons.
patterning along the anterioposterior axis at the level of the emerging In fact, Wnt4 was recently shown to be directly regulated by Pax2
kidney, is also required for renal development. Triple mutants for during renal vesicle formation . Interestingly, subsequent renal
Hoxa11/Hoxc11/Hoxd11 show a complete loss of metanephric kidney tubule differentiation is not compatible with activated, stabilized b-
formation . catenin, implying the need for a downregulation of Wnt signaling in
Pax2, Six1, Six2 and Six4 have been implicated in regulating the later stages .
expression of Gdnf to stimulate ureteric bud outgrowth , whereas In conclusion, the specification along the anterioposterior and
Gata3 has been suggested as a transcriptional regulator of Ret mediolateral axes to induce formation of MM and UB and to drive
expression downstream of Pax2/8 in the developing nephric duct . kidney morphogenesis requires the activation of multiple pathways.
Interestingly, the Hox11 paralogous proteins have been shown to The relationship between these proteins and their interactions are
form a complex with Pax2 and Eya1 to directly activate expression of complex and still incompletely understood.
mine the peptide motifs and protein machinery that direct nucleus, where it activates activator protein 1 (AP-1)–de-
Gli and Glis proteins to the cilia to fully understand the pendent transcriptional pathways [21,22]. Cell cycle regu-
signal-dependent modiﬁcations of these proteins. lation via p21 induction can also occur by direct activation
of JAK-STAT signaling by PKD1 and 2 . In addition,
Connecting the cilium with the nucleus processing of the C-terminal tail of PKD1 might be trig-
Localization of transcriptional regulators to cilia and the gered in response to mechanosensation of ﬂuid ﬂow in
cell membrane is not limited to the Gli and Glis families. renal tubules, resulting in ciliary-nuclear translocation
Additional pathways allow the cilium to inﬂuence nuclear together with its interactors STAT6 and P100 .
gene transcription: the proteins encoded by PKD1 and Because no kidney malfunction has been reported in mice
PKD2, polycystin-1 and polycystin-2, are transmembrane with mutated Id2 or Stat6 genes, the physiological import-
glycoproteins that interact with one another and mediate a ance of these proteins in renal disease is not clear. Further-
variety of complex formations. PKD2 binds to and seques- more, Pkd1-mutant mice show ectopic Pax2 expression,
ters Id2, a basic helix–loop–helix (bHLH) transcription and deletion of Pax2 reduces cyst growth in Pkd1-deﬁcient
factor that regulates cell proliferation by suppressing mice, suggesting that PKD1 represses Pax2 in an, as yet,
p21, a CDK inhibitor. By preventing nuclear localization unknown manner .
of Id2, PKD2 inhibits cell cycle progression by upregulating Similarly, polyductin (also known as ﬁbrocystin)
p21 . Interestingly, this interaction requires the phos- encoded by PKHD1 is subject to proteolytic cleavage, which
phorylation of polycystin-2. This phosphorylation reaction is in this case dependent on Ca2+- signaling . Its large
is dependent on PKD1, which can itself be proteolytically extracellular domain is shed from the cilium, whereas the
cleaved, and its processed C-terminal tail can enter the intracellular part has been suggested to enter the nucleus
represents the functional unit of the kidney and consists of a glomerulus, a proximal tubule, the loop of Henle and a distal tubule connected to the collecting duct. The initial
blood filtration occurs inside the glomerulus, which harbors a dense capillary tuft, podocytes and supporting mesangial cells, surrounded by Bowman’s capsule. (d) Blood
plasma passes through the fenestrated endothelium, the glomerular basement membrane, and ultimately through the slit diaphragm between interdigitating podocyte foot
processes, which acts as a macromolecular filter, into the urinary space.
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Figure 1. Schematic representation of a primary cilium. A primary cilium consists of a central axoneme made of microtubules enclosed by a distinct cell membrane. Several
structural elements such as the periciliary membrane, the transition fibers and basal bodies form a selective barrier at the entrance of the cilium and create a unique
environment that allows for compartmentalization. Protein products of genes implicated in polycystic kidney disease (‘cystic proteins’) localize to the basal body,
membrane or axoneme of the cilium. Cilia are sensory organelles that can probe the extracellular environment, but they also act as signaling centers. Bending of the cilium
by renal tubular flow causes an intracellular Ca2+ influx that sets off a variety of signaling cascades. Components of the Hedgehog (and other) signal transduction
pathway(s) have been shown to depend on ciliary localization. The binding of the secreted Sonic hedgehog protein (Shh) to its receptor Patched, and the Smoothened-
mediated processing of the Gli transcription factors has been detected in the cilium. The Gli transcription factors can move from there to the nucleus to regulate gene
expression in response to Hedgehog signaling, either activating or repressing transcription (GliA or GliR). Other transcription factors, such as Stat6 and Glis2, and
fragments of ‘cystic proteins’ have also been reported to localize to the cilium and the nucleus.
after cleavage by gamma-secretase, in a manner analogous Maintenance of renal epithelial morphology
to Notch processing . Likewise, inversin, a protein In contrast to the putative physiological role of nuclear
implicated in nephronophthisis, has been proposed to ciliary protein fragments, the function of b-catenin in
localize to the nucleus [28,29]. Moreover, the ‘cystic transcriptional regulation downstream of canonical Wnt
protein’ CEP290 binds to and modulates the activity of signaling is ﬁrmly established . Canonical Wnt sig-
the transcription factor ATF4 . These results together naling is required during early kidney development,
suggest that the cleaved fragments of various ciliary whereas the noncanonical planar cell polarity (PCP) path-
proteins can have a co-activator/co-repressor-like role in way is required for the proper alignment of cell divisions
transcriptional regulation. However, it is not yet clear if during epithelial tubule elongation [32–34]. Noncanonical
these events occur in vivo and any functional consequences Wnt signaling is independent of b-catenin, but shares
for kidney development and homeostasis remain to be several other pathway components such as Frizzled and
elucidated. Dishevelled with the canonical Wnt signaling pathway.
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Furthermore, it has been suggested that the ciliary protein but distinct functions in renal and gonadal development
inversin triggers the switch between canonical and non- . In particular, the absence of the +KTS form in Frasier
canonical Wnt signaling, which could occur in response to syndrome causes defects in podocyte function . At least
urine ﬂow [28,35]. In this respect, it is noteworthy that three ‘podocyte genes’ are regulated by WT1 directly:
inversin interacts with b-catenin . It is conceivable that podocalyxin, nephrin and Pax2. The relationship between
adult kidney homeostasis requires a ‘shut-down’ of the Pax2 and WT1 is complex, and Pax2 expression in podo-
canonical Wnt pathway after organogenesis is completed, cytes has been linked to repression of WT1. Interestingly,
whereas the PCP pathway confers the necessary spatial ectopic Pax2 expression in glomerular podocytes has been
information for appropriate mitotic spindle orientation in found in several pathological conditions. Persistent trans-
renal tubules. Consequently, overexpression of a constitu- genic expression of Pax2, which is normally repressed
tively active form of b-catenin in mice causes cystic renal during terminal differentiation of renal epithelial cells,
disease . Although there is evidence for disrupted has been shown to disrupt kidney function and morphology
planar cell polarity in polycystic kidneys , a require- (cyst formation and absence of foot processes). These ﬁnd-
ment for ciliary localization has not been demonstrated for ings have been extended by another mouse model that
components of the Wnt signaling pathway . allows inducible expression of Pax2 in fully mature podo-
We are beginning to gain a clearer insight into the cytes of adult kidneys, which leads to dedifferentiation and
transcriptional regulation of the ‘cystic genes’ themselves, establishes a causal relationship between ectopic Pax2
in particular Pkd2 and Pkhd1. Recent evidence from mice activation and glomerular disease .
shows that the homeobox transcription factor hepatocyte The human nail-patella syndrome, which is often associ-
nuclear factor-1b (Hnf1b), also known as transcription ated with renal disease, is caused by mutations in the LIM
factor 2 (Tcf2), regulates Pkd2 (but not Pkd1) and Pkhd1 homeodomain transcription factor LMX1B . LMX1B
gene expression by binding directly to their promoters. has been shown to regulate the expression of a3(IV) and
Consequently, deletion of HNF1b in murine kidneys leads a4(IV) collagen chains directly; these are essential com-
to cyst formation and the downregulation of Pkd2, Pkhd1, ponents of the glomerular basement membrane and of
Ift88 (also known as Tg737 or Polaris) and Umod; the latter podocin, a nephrin-binding membrane protein implicated
two genes are involved in the development of renal cysts in steroid-resistant nephrotic syndrome . A recent
. In humans, mutations in HNF1b cause the RCAD comprehensive study addressed the role of Lmx1b in glo-
syndrome (renal cysts and diabetes) . A similar phe- merular disease. Lmx1b-deﬁcient podocytes fail to form
notype was observed in mice with a targeted inactivation of foot processes and slit diaphragms, which leads to protei-
the transcriptional coactivator Wwtr1/TAZ . nuria. Moreover, podocyte-speciﬁc inactivation of Ldb1,
In summary, the mechanisms controlling proliferation, which interacts with Lmx1b biochemically, also results
differentiation and apoptosis of renal epithelial cells seem in a podocyte phenotype with gradual loss of foot processes
to entail complex interactions between ciliary proteins and .
transcriptional regulators with cross-talk on multiple Furthermore, a subset of mutations in the forkhead
levels. However, the functional signiﬁcance this cross-talk transcription factor FOXC2 underlying the human lym-
has for kidney physiology needs further analysis. phedema-distichiasis syndrome have been reported to be
associated with renal malfunction . Indeed, knockout
Glomerular diseases: the podocyte takes center stage studies in mice have conﬁrmed a role for Foxc2 in podocyte
Glomerular diseases encompass a wide range of pathologi- development [47,48]. Promising candidate genes for unex-
cally deﬁned syndromes that account for most cases of plained forms of human inherited glomerular disease in-
ESRD . The glomerulus serves a primary function in clude MAFB, which encodes a basic domain leucine zipper
ﬁltering the urine from the blood, and failure in this transcription factor, and transcription factor 21 (TCF21)
process might result in proteinuria and kidney failure also known as Podocyte-expressed 1 (POD1), which
(see Figure I in Box 1). Common diseases, such as diabetes, encodes a bHLH transcription factor. Mouse models with
hypertension, autoimmune diseases and toxic drug intake MafB or Tcf21/Pod1 gene disruptions affect podocyte func-
can cause glomerular insults that mainly affect the podo- tion because of diminished expression of podocin and
cyte, a highly specialized visceral epithelial cell type. nephrin [49–51]. Moreover, the Notch pathway has been
Mutations in genes encoding structural components of shown to be essential for podocyte development . The
the podocyte foot processes, slit diaphragms or glomerular transcriptional regulator RBPjk, which can form hetero-
basement membrane (such as nephrin, podocin, collagen dimeric complexes with other bHLH transcription factors,
type IV and b2-laminin) have long been known to be causes functions downstream of Notch signaling. Interestingly,
of glomerulopathies [40,41], but the transcriptional regu- genetic deletion of RBPjk in podocytes delays the pro-
lation of these genes in renal physiology and disease is just gression of glomerular disease, providing another example
beginning to become clear . that termination of the developmental program is import-
Wilms’ tumor protein 1 (WT1) is a zinc-ﬁnger transcrip- ant to prevent renal disease . Additional candidate
tion factor with several roles in kidney development and genes for the development of glomerular disease encode
function . The human Wilm’s tumor-aniridia-genitour- the zinc ﬁngers and homeoboxes (ZHX) transcription fac-
inary anomalies-mental retardation syndrome (WAGR) tors, which were reported to be expressed in podocytes and
and the Denys-Drash and Frasier syndromes are all caused to regulate numerous functionally important podocyte
by different mutations in WT1. The two main WT1 splice genes . In the future, more genes will join the ranks
isoforms referred to as ÀKTS and +KTS, have overlapping of regulators of podocyte function, as efforts are currently
TIGS-649; No of Pages 11
Review Trends in Genetics Vol.xxx No.x
being made to identify glomerulus-speciﬁc transcripts on a ﬁbrosis [56,57]. Fibrosis is characterized by an excessive
large scale . Like all other renal epithelial cells, podo- accumulation and deposition of extracellular matrix
cytes possess cilia. However the importance of cilia sig- (ECM) that progressively leads to the destruction of func-
naling for podocyte function remains to be studied. tional nephrons. The majority of ECM is produced by
As alluded to earlier, the most common cause of kidney a-smooth muscle actin expressing myoﬁbroblasts .
failure is diabetic nephropathy. High glucose concen- Myoﬁbroblasts are believed to form through phenotypic
trations in the blood induce proliferation of another glo- transition of existing interstitial ﬁbroblasts, mesangial
merular cell type, the mesangial cell (see Figure I in Box 1). cells, or migration of more distant cells into the kidney
Mesangial cell proliferation is a hallmark feature of glo- . However, there is increasing evidence further sup-
merulosclerosis, and has been correlated with production ported by the analysis of Glis2 mutant kidneys that myo-
of angiotensin II, transforming growth factor b (TGF-b), ﬁbroblasts can also originate from renal epithelial tubules
and platelet-derived growth factors (PDGFs) . In through epithelial-to-mesenchymal transition (EMT)
particular, the JAK–STAT pathway mediates a signiﬁcant [60,61] (Figure 2). Although EMT is an essential process
part of the proliferative effects of PDGF and ANG II. JAK required for metazoan embryogenesis, it is responsible
proteins are cytoplasmic tyrosine kinases, which once for the detrimental effects seen under pathophysiological
activated phosphorylate STAT transcription factors, conditions of organ ﬁbrosis and cancer metastasis [62,63].
resulting in their nuclear translocation and the activation Loss of Glis2 or other ﬁbrotic responses induce expression
of responsive promoters . Furthermore, Y-Box protein of the zinc ﬁnger transcription factor Snail, which in turn
1, which has transcriptional regulatory activity, was impli- represses E-cadherin and Cadherin-16 expression. Down-
cated as a mediator of PDGF-B–induced mesangial cell regulation of cadherin leads to a loss of cell adhesion and
proliferation . Inhibition of this pathway might thus cell polarity. Interestingly, Snail does not directly repress
provide an interesting target for therapeutic intervention. Cadherin-16, but rather reduces expression of its activator
HNF1b. Ectopic activation of Snail in adult mice has been
Renal ﬁbrosis: the ﬁnal stage of chronic kidney disease shown to be sufﬁcient to drive EMT and cause renal
Regardless of the initial cause, virtually all types of ﬁbrosis. Moreover, Snail upregulation can be observed
chronic kidney disease are complicated by the histological in patients with ﬁbrotic kidneys . In addition, Gli1
appearance of glomerulosclerosis and tubulointerstitial was recently shown to regulate the expression of Snail,
Figure 2. Signaling pathways in renal fibrosis. Renal epithelial tubules are formed by mesenchymal-to-epithelial transition (MET) from the metanephric mesenchyme
during development, whereas the reverse process, epithelial-to-mesenchymal transition (EMT), is associated with the loss of cell polarity and adhesion leading to kidney
fibrosis. During EMT, epithelial cells lose apical-basal characteristics and expression of cell adhesion molecules like E-cadherin, acquire mobility and adopt a fibroblast-like
morphology. Factors such as TGFb, USAG-1, Snail, Gli1, KAP1 and CBF-A promote EMT and the appearance of myofibroblasts that are characterized by the expression of
genes such as FSP1 and a-SMA (pink). In healthy renal tubules, proteins such as BMP7, KCP, Glis2 and HNF1b prevent fibrosis by stabilizing the expression of cadherins and
the epithelial phenotype and inhibiting ectopic Gli1 or Snail activation (purple).
TIGS-649; No of Pages 11
Review Trends in Genetics Vol.xxx No.x
and Gli1-mediated Snail activation (followed by E-cad- technologies, will be useful to elucidate transcriptional
herin downregulation) drives transformation of epithelial regulatory networks governing kidney physiology. In this
cells in tumor progression . These results emphasize respect, it is reassuring to see the publications of the ﬁrst
the requirement for repression of Gli-responsive promo- renal studies driven by a systems biology approach [72,73].
ters to prevent EMT. Fibroblasts created through EMT in Although we have learned much about early events
the kidney express the FSP1 gene (known as S100a4 in the during metanephric development, there is still a lack of
cancer literature), which encodes ﬁbroblast-speciﬁc knowledge regarding later events such as patterning of
protein 1. The transcriptional regulators, CArG box-bind- nephric tubule segments, and self-renewal of the mesench-
ing factor-A (CBF-A) and KRAB-associated protein 1 ymal progenitor pool. Furthermore, it is becoming increas-
(KAP-1) bind to distinct DNA motifs in the promoter of ingly clear that ‘terminally’ differentiated cell types in the
FSP1 and activate its transcription. Similar binding mature kidney might not exist. This is best underscored by
sites can be found in the promoters of several other recent observations of the reactivation of developmental
EMT-associated transcripts such as Twist, Snail, E-cad- transcription factors in renal disease progression, as
herin, vimentin, a1(I)collagen and a-smooth muscle actin, shown for Pax2 and RBPjk in polycystic kidney and glo-
all of which are activated by the CBF-A/KAP-1 complex merular disease and for Gli1 and Snail in renal ﬁbrosis.
[66,67] (Figure 2). Thus, adult kidney homeostasis seems to rely on active
Our understanding of the transcriptional network con- silencing of developmental gene expression programs, as
trolling EMT in different organ systems is improving fast. It exempliﬁed by the analysis of Glis2 function. The under-
is generally thought that TGF-b and its downstream SMAD appreciated cellular plasticity in the kidney, however,
signaling play an essential role in most forms of chronic might open up untapped sources for the treatment of
kidney disease. Expression of TGF-b in transgenic mice chronic kidney disease.
promotes EMT and ﬁbrosis, whereas inhibition of TGF-b In this respect, it will be of tremendous interest to eluci-
by different approaches (including overexpression of the date the molecular mechanisms of cilia signaling beyond its
inhibitory Smad7) prevents it [60,68]. Another member of proposed function as a mechanosensor of renal tubular ﬂow.
the TGF-b superfamily, BMP7, which is required for early Furthermore, studying the regulation and necessity of cili-
kidney development, has the opposite effect: it counteracts ary localization for various signaling pathways and its func-
EMT and prevents ﬁbrosis [68,69]. Furthermore, modiﬁers tional importance in kidney development and disease has
of BMP signaling, such as the enhancer KCP and the BMP already begun to open up a new ﬁeld of investigation. For
antagonist USAG-1, have been shown to improve or worsen most transcription factors that are important during early
the formation of ﬁbrous tissue, respectively [69,70]. kidney organ induction and patterning, their role during
Thus, molecular mechanisms underlying kidney ﬁbrosis later morphogenetic stages is still not clariﬁed. Thus, it
suggest that renal ﬁbrosis can be thought of as reversal of will be important to systematically take advantage of
early kidney development. However, we have much to conditionally and temporally controlled gene disruption
learn about the transcriptional network that drives the approaches in mice to illuminate their speciﬁc function in
formation of renal epithelial cells through mesenchymal- mature nephrons and during kidney disease. Finally, con-
to-epithelial transition (MET) during development. This ditional mutagenesis and genetic screens in human patients,
information will be useful in designing novel therapeutic zebraﬁsh or other model organisms will continue to yield
strategies to reverse kidney ﬁbrosis (Figure 2). novel genes required for kidney organ development.
Clearly a lot still needs to be learned about organ de-
Concluding remarks and open questions velopment and physiology in this fascinating model system
Transcription factors not only serve as genetic markers for to open new avenues for therapeutic interventions in the
speciﬁc cell populations but more importantly orchestrate battle against the increasing pandemic of chronic kidney
the genetic program within each cell. Therefore, they disease (Box 3).
provide useful entry points to decipher the cis-regulatory
networks that underlie the coordinated expression of
speciﬁc sets of genes to create the various renal cell types Box 3. Outstanding questions and future directions
required for kidney function. What are the gene expression signatures of the specialized renal cell
Over recent years, many transcriptional regulators of types in the adult kidney, and what is their relationship to renal
kidney development have been identiﬁed, but most of the physiology and tissue homeostasis?
target genes controlled by these transcription factors What is the lineage relationship of the differentiated renal cell types
and what is the extent of renal cellular plasticity in the adult organ?
remain elusive (with few exceptions). Likewise, the hier- What can be learned from the identification of the transcriptional
archical relationships between the individual regulators networks downstream of cilia signaling in the adult kidney?
are thus far difﬁcult to assess. In the future, it will be Why is only part of the developmental program reactivated in renal
important to move beyond descriptive approaches of loss- injury and repair and how do these processes differ from renal
of-function phenotypes for single genes. Time courses and
What are the pathways that terminate mesenchymal-to-epithelial
high-throughput validation of the expression proﬁles transition during renal development and is epithelial-to mesench-
obtained from loss-of-function studies should help to ymal transition in kidney fibrosis reversible?
identify gene expression signatures that are important Do true adult renal stem cells exist which could be utilized for renal
for kidney development and disease [48,71,72]. In vivo replacement and repair therapy after injury?
What are the renal disease-associated transcriptional programs
chromatin immunoprecipitation (ChIP) studies, in combi-
resulting from ageing, diabetes, obesity and hypertension?
nation with genomics, bioinformatics and proteomics
TIGS-649; No of Pages 11
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Acknowledgements 27 Kaimori, J.Y. et al. (2007) Polyductin undergoes notch-like processing
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cited because of space constraints. The authors thank Petra Riedinger for 956
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