REVIEWA New Role for the Renin-angiotensin System in the Development of
the Ureteric Bud and Renal Collecting System
Ihor V. Yosypiv

Division of Pediatric Nephrology, Department of Pediatrics,
Tulane University Health Sciences Center, New Orleans, USA(Received for publication on April 22, 2008)(Accepted for publication on June 19, 2008)

Abstract. The renin-angiotensin system (RAS) plays a critical role in kidney development.
Mutations in the genes encoding components of the RAS or pharmacological inhibition of
RAS in mice or humans cause a spectrum of congenital abnormalities of the kidney and urinary tract (CAKUT). The observed defects include renal vascular abnormalities, abnormal
glomerulogenesis, renal papillary hypoplasia, hydronephrosis, aberrant ureteric bud (UB)
budding, duplicated collecting system and renal tubular dysgenesis. Little is known about
the potential role of Ang II and its receptors in the morphogenesis of the UB and renal collecting system. This review emphasizes a novel role for the RAS in the development of
the UB, collecting ducts and renal medulla. We observe that UB and surrounding stroma
express angiotensinogen and Ang II AT1 receptors (AT1R) in vivo . Ang II stimulates UB cellbranching in collagen gel cultures in vitro and induces UB morphogenesis in intact whole
embryonic metanephroi grown ex vivo . In contrast, treatment of metanephroi with the AT1R
antagonist candesartan inhibits UB branching. In addition, Ang II induces tyrosine phosphorylation of the epidermal growth factor receptor (EGFR) in UB cells. Furthermore, Ang
II-stimulated UB morphogenesis is abrogated by inhibition of EGFR tyrosine kinase activity. In summary: 1) Ang II, acting via the AT1R, stimulates UB branching; 2) This processdepends on tyrosine phosphorylation of the EGFR. Together, these data indicate that cooperation of AT1R and EGFR signaling performs essential functions during renal collecting
system development via control of UB branching morphogenesis. (Keio J Med 57 (4) : 184－
189, December 2008)
Key words: kidney development, renin-angiotensin, metanephros, ureteric bud

Introduction
Congenital abnormalities of the kidney and urinary
tract (CAKUT) are the major cause of renal failure inchildhood.1 Many CAKUT have a genetic basis and areassociated with hereditary human syndromes.2 The inheritance pattern of some CAKUT (autosomal-dominantor recessive polycystic kidney disease) is well known.3
In other nonsyndromic CAKUT (obstructive uropathy,
vesico-ureteral reflux, kidney aplasia, duplex kidneys),the hereditary mechanisms remain to be determined. In
this respect, recent discovery of a number of genes involved in coordination of metanephric development pro-vided a further impulse to explore in depth the pathogenesis of the CAKUT.
Overview of Metanephric Kidney Development
The development of the metanephric kidney begins
when the nephric duct (ND) gives rise to ureteric bud(UB) on embryonic (E) day E10.5 in mice and E28 inhumans (Fig. 1). The initial events controlling UB induction are regulated by numerous transcription factors
and signaling molecules that are expressed in a specificspatial and temporal patterns.4 Signals from the mesenchyme induce the UB to originate from the ND, invade

Presented at the 1562nd meeting of the Keio Medical Society in Tokyo, May 9, 2008.
Corresponding Author: Ihor V. Yosypiv, M.D., Associate Professor, Department of Pediatrics, SL-37, Tulane University Health Sciences Center, New Orleans,
LA70112, Tel: +1–504-988-5377, Fax: +1–504-988-1852, E-mail: iiosipi@tulane.edu
184

Keio J Med 2008; 57 (4): 184－189

185

Fig. 1 Gene regulatory networks in kidney development. The nephric duct is formed from the intermediate mesoderm and extends
caudally. On E10.5 in mice and E28 in humans, nephric duct forms an outgrowth, the ureteric bud (UB), which invades themesenchyme. UB induces mesenchyme to undergo patterning into two compartments: induced (metanephrogenic) mesenchyme
and stroma. Metanephrogenic and stromal mesenchymal compartments interact reciprocally with the UB to form the metanephros.
Multiple gene regulatory networks have been shown to regulate UB elongation, branching and nephron formation. Robo2, Slit2,
BMP4, FoxC1/C2 and AT2R act to restrict GDNF expression anteriorly and specify correct site of UB outgrowth from the nephric duct.
GDNF/c-Ret/Wnt11 pathway is the major positive regulator of UB development. Angiotensinogen (AGT) and Ang II are novel stromal
factors that regulate UB morphogenesis. Ang II, acting via the AT1R, inhibits Spry1 expression and thereby releaves inhibition of
signaling via the GDNF/c-Ret/Wnt11 pathway. Acting via the AT2R, Ang II upregulates Pax2. This stimulates UB branching.

the mesenchyme and then branch repeatedly by a process
called branching morphogenesis (Fig. 2). Initial generations of UB branches will be remodeled into the ureterand collecting system. Subsequent generations of UB
branches will differentiate into collecting ducts. Collecting ducts will subsequently undergo patterning to contribute importantly to the renal papilla and medulla.
Each UB tip is capable of inducing the adjacent metanephrogenic mesenchyme (MM) to undergo mesenchymal-to-epithelial transition (MET) and form nephrons(from the glomerulus to the distal tubule).1 2 Therefore,
UB branching morphogenesis is critical in determining
total nephron number, proper kidney size and structure.
The GDNF/c-Ret/Wnt11 signaling pathway is a major
positive regulator of UB induction and branching in themetanephros (Fig. 1).5 Glial-derived neurotrophic factor(GDNF)
GDNF) is released from the MM and interacts with the
GDNF
c-Ret tyrosine kinase receptor expressed in the UB tip
cells to induce branching.6 GDNF/c-Ret and Wnt11 cooperate to maintain continued UB branching.6, 7 The activity of the GDNF-c-Ret-Wnt11 pathway is inhibited by
Spry1.8 The correct site of initial UB induction is speci-

fied by restricting GDNF expression within the specified
domain of the mesenchyme by Robo2/Slit2/FoxC1/
FoxC2.9- 11 Interestingly, mutations in the genes expressed in the stromal mesenchyme compromise both
UB branching and MET.13, 14 Therefore, even subtle aberrations in reciprocal interactions among the UB, MM
and stroma have profound effect on the ultimate development of the kidney and appearance of CAKUT.
Role of the Renin-angiotensin System
in Metanephric Kidney Development
The developing metanephric kidney expresses all thecomponents of the renin-angiotensin system (RAS).15-17
The activity of the intrarenal RAS is high during fetal
and neonatal life and declines during postnatal maturation. Renin mRNA and angiotensin (Ang) II levels are
remarkably higher, respectively, in newborn than adultkidneys.1 5, 1 8 AT1 (AT1R) and AT2 (AT2R) receptors areabundantly expressed in the nephrogenic area.19 The ontogenic expression of AT1R and AT2R in the metanephrosdiffers. AT2R is expressed earlier than AT1R, peaks during

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Yosypiv IV: Angiotensin in Kidney Development

Fig. 2 Ureteric bud branching morphogenesis in the mouse. Ureteric bud (UB) emerges from the nephric duct on embryonic (E) day
E10.5. Metanephros isolated on E11.5 from Hoxb7-GFP transgenic mouse embryo and grown ex vivo for 48 hours. Hoxb7 promoter
directs expression of green fluorescent protein (GFP) to the UB. The number of branching structures increases progressively withtime.

fetal life and rapidly declines postnatally.19,20 AT1R expression increases during gestation, peaks perinatallyand declines gradually thereafter.2 0 Spatially, AT1R ispresent in glomeruli, in distal and proximal tubules,
whereas AT2R is expressed in mesenchymal cells adjacent to the UB stalk.
Genetic inactivation of the RAS components in miceor pharmacologic antagonism of the RAS cause a spectrum of abnormalities in the development of the ureter,
renal pelvis and papilla.2 1 -2 7 Angiotensinogen, angiotensin-converting enzyme (ACE) or AT1R-deficient micemanifest hydronephrosis, hypoplastic medulla and papilla. Functionally, ACE and AT1R null animals also have a
reduced ability to concentrate urine. 24, 25 Elegant studies
from Dr. Ichikawa’s laboratory have suggested that antagonism of AT1R signaling in ureteral smooth muscle
cells impairs smooth muscle development in the ureter
as well as its peristalsis.2 8 Treatment with ACE inhibitors or AT1R antagonists during gestation or postnatal
metanephrogenesis leads to renal tissue dysplasia, a decrease in the number and size of glomeruli, renal arteries
and delay in glomerulogenesis.2 9-31 Use of ACE inhibitors and AT1R blockers in humans cause oligohydramnios and anuria.3 2, 33 Therefore, these drugs should not be
used by pregnant women.
AT2R is expressed between the ND and the metanephrogenic mesenchyme anterior to the normal branchingsite in wild-type mice on E11.3 4, 3 5 AT2R-mutant micedemonstrate a decrease in the rate of apoptosis of mesenchymal cells around the nascent UB.35 Mutations in the

AT2R gene in mice are associated with increased incidence of duplex ureters and vesicoureteral reflux.34 Thus,
it is conceivable that AT2R may mark mesenchymal cells
destined to undergo apoptosis and that absence of timely
apoptosis of these cells may cause an aberrant UB budding and lead to duplicated ureters. In addition, AT2R
may act as restricting signal to limit anterior expansionof the GDNF domain (Fig. 1).
Mutations in the genes encoding for angiotensinogen,renin, ACE or AT1R in humans lead to renal tubular dysgenesis (RTD). 36, 37 In RTD, renal cortex exhibits a paucity of proximal tubules. In the medulla, collapsed collecting ducts and abundant interstitial fibrosis are observed.3 7 Importantly, RTD in humans is characterized
by perinatal death due to anuria combined with pulmonary hypoplasia. The more severe outcome in humans
than in mice without the functional RAS may be due tothe temporal difference in completion of nephrogenesis.
In mice, nephrogenesis is completed 2 weeks after birth,whereas in humans- at 38 weeks of gestation. Collectively, the observed abnormalities in UB/medullary development imply that UB-derived structures are targets
for Ang II actions during metanephric development inboth mice and humans.
Role of the Renin-angiotensin System
in Ureteric Bud Morphogenesis
To examine the importance of the RAS in UB development, we recently tested the hypothesis that Ang II, act-

Keio J Med 2008; 57 (4): 184－189

ing via AT1R, stimulates UB branching morphogenesis.
Immunohistochemistry demonstrated that angiotensinogen and AT1R are present in both UBs and the stromal
mesenchyme on embryonic (E) day E12 in the mouseand that their expression increases progressively from
E12 to E16.38 Importantly, AT1R immunoreactivity waspresent on both luminal and basolateral aspects of UB
branches.38 Since juxtaglomerular renin-producing cells
originate from the mesenchyme on E11-E12, at a time
when UB branching is just beginning,39 Ang II may begenerated locally in the mesenchyme to act in a paracrine
fashion on the adjacent AT1R-expressing UBs to regulate
branching. AT1R expressed in the mesenchyme may mediate mesenchymal Ang II signaling to stimulate UB
branching. Since fibroblast growth factor (FGF) 7 is expressed in the stromal mesenchyme, and that Ang II increases FGF7 mRNA levels in luteal cells,4 0 it is conceivable that Ang II may regulate UB branching via induction of FGF7 in the stroma.
Given that cultured UB-derived cells (UB cells) maintain expression of AT1R mRNA and protein, we next investigated the direct role of Ang II and AT 1R in UB
branching morphogenesis in UB cells3 8. Because utilization of UB cell culture model allows to avoid confounding influence of the mesenchyme, it is more relevant to define the direct role of Ang II in UB development. Ang II (10-5 M) increased the number and complexity of UB cells processes grown in three-dimensional
collagen matrix gels. Ang II-induced increase in UB cellbranching was prevented by AT1R antagonist candesartan (10-6 M). These data demonstrate that Ang II stimulates cell process formation and branching cord extension in UB cells in vitro via activation of the AT1R.
We further tested the role of Ang II in UB branchingmorphogenesis in the intact metanephric kidney where
mesenchymal-epithelial interactions are intact. To determine the role of Ang II in early stages of UB development in the whole metanephros, we utilized embryonickidneys obtained from Hoxb7-GFP transgenic mice
which express green fluorescent protein (GFP) exclusively in the UB.41 Quantitative analysis of UB branching morphogenesis demonstrated that exogenous Ang II
increased the number of UB tips and branch points compared to control.4 2 To examine the role of endogenous
Ang II and AT1R in UB branching in the metanephros,
we utilized the AT1R antagonist candesartan. Treatmentof E11.5 metanephroi with candesartan (10- 6 M) decreased the number of UB tips and branch points compared to control. These findings demonstrate that Ang
II, acting via the AT1R, stimulates UB branching morphogenesis in the intact metanephros.
The findings of angiotensinogen and renin in the stroma, and of AT1R in the UB epithelia during active UB
branching in vivo, together with AT1R-mediated increase
in UB branching in vitro suggest that angiotensinogen

187

and Ang II may represent novel stromal factors that regulate UB branching morphogenesis (Fig. 1). It will be
crucial to delineate the effects of the AT1R null mutation
on expression of stromal factors necessary for proper UB
branching (Foxd1, FGF7, Wnt2b, pbx, p57 and retinoic
acid receptors). This will allow better understanding of
the mechanisms regulating the development of the renal
medulla and papilla.
Collectively, our data suggest that papillary hypoplasia
in RAS-deficient mice is due, in part, to an intrinsic defect in UB branching and aberrant development of therenal medulla. Indeed, Ang II may regulate multiple
steps of renal collecting system development. During
early metanephric development, Ang II is formed in thestromal mesenchyme and acts on AT1R and AT2R locatedon UBs to stimulate branching (Fig. 1). Later in metanephric development, Ang II stimulates patterning of
UB-derived collecting ducts, pelvis and ureter.
Given that stimulation of the epidermal growth factor
receptor (EGFR) induces branching morphogenesis inmurine inner medullary collecting duct (IMCD3)cells43, 44 and that renal papilla of angiotensinogen- andAT1R-deficient mice exhibits reduced EGF mRNA levels,45 we next investigated the contribution of EGFR activation to Ang II-induced UB branching. Ang II increased tyrosine phosphorylation of EGFR in UB cells.42
Inhibition of EGFR tyrosine kinase activity abrogatedAng II-induced cell process formation in UB cells and
UB branching in the intact metanephros.4 2 These findings indicate that cooperation of AT1R and EGFR signaling promotes the development of the renal collecting
system.
Ang II can stimulate UB branching directly or throughinteraction with other factors present in the metanephrogenic mesenchyme, stroma or the UB that are known toregulate UB morphogenesis (Fig. 1). For example, Ang
II may stimulate Pax2 present in the UB and thereby enhance UB branching. These possibility is supported by
the ability of Ang II to increase Pax2 expression in metanephric kidney.4 6 Since GDNF/c-Ret/Wnt11 signaling
plays a major role in promoting UB morphogenesis, werecently examined the role of this pathway in Ang II-induced UB branching. Our preliminary findings demonstrate that Ang II enhances GDNF, c-Ret and Wnt11 expression in the UB tip cells and indicate that activationof this pathway by Ang II plays a critical role in Ang IImediated signaling to stimulate UB development. 4 7
Since Spry1 is a negative regulator of the GDNF/
c-Ret/Wnt11 pathway, we tested the hypothesis that Ang
II inhibits Spry1 gene expression. Our preliminary data
indicate that Ang II downregulates Spry1 expression in
the UB in the intact embryonic kidneys grown ex vivo.47
Furthermore, downregulation of Spry1 expression is prevented by antagonism of the AT1R. Therefore, Ang II
may stimulate the GDNF/c-Ret/Wnt11 pathway indirectly

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Yosypiv IV: Angiotensin in Kidney Development

via repression of Spry1 (Fig. 1).
The role of AT2R in UB branching is beginning toemerge. AT2R-mutant mice exhibit ectopic ureteral budding and duplicated collecting systems.34 This suggeststhat AT2R inhibits aberrant UB budding. It is conceivable that unopposed stimulation of AT2R in AT1R- mutant mice may hinder UB branching. Our preliminary
data demonstrate that AT2R is expressed in UB branches
during mouse nephrogenesis in vivo48 and that AT2R antagonist PD123319 inhibits Ang II-induced cell process
formation in UB cells cultured in three-dimensional collagen matrix gels.49 The ultimate effect of Ang II on UB
branching may depend on the balance between AT1Rand AT2R-mediated actions.
The signaling events linking Ang II receptors to UB
branching morphogenesis remain to be determined. Several signaling pathways, including MAP kinase andPI3K/Akt, have been shown to mediate the effects of
AT1R on renal cell proliferation.43 Thus, one of the possible mechanisms leading to Ang II-stimulated tyrosine
kinase signaling may involve EGFR- or c-Ret-mediatedstimulation of MAP kinase and PI3K/Akt pathways.4, 4 3
AT2R-dependent mesenchymal apoptosis3 5 may result
from activation of MAP kinase phosphatase 1 leading toinactivation of ERK1/2.50 AT2R-dependent activation of
Pax2 in whole metanephroi and mesenchymal cells is
mediated by JAK2/STAT pathway23.
In addition to stimulating UB morphogenesis, paracrine distal nephron RAS may regulate the expression ofrenal function genes, control terminal differentiation of
the collecting duct cells and promote acquisition of theirmature physiological function. These possibilities aresupported by the following observations: 1) Ang II, acting via AT1R, regulates urinary concentrating ability;2 52) In the adult animal, Ang II acts via basolateral AT1R
to stimulate luminal alkalinization in rabbit cortical collecting duct;51 3) In rat collecting duct, Ang II regulates
H+-ATPase and basolateral K channel activities.52, 53
Perspectives
Future studies investigating the effect of UB- and stromal mesenchyme-specific inactivation of angiotensinogen, AT1R and AT2R on urinary system phenotype andthe expression of the critical gene networks known toregulate UB branching, collecting duct/medullary/renalcollecting system/ureteral patterning will provide essential information regarding the nature of events culminating in the formation of the mature metanephros.
Acknowledgements
The author would like to thank Mercedes Schroeder,
Mary Kate Boh, Melissa Spera, Renfang Song and Samir
El-Dahr for assistance with the original studies. The

original work was supported by NIH Grant P20
RR17659 and NIH/NIDDK Grant DK071699-01 (Ihor
Yosypiv).
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