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. 2004 Jul-Aug;1(1):26–32. doi: 10.4161/org.1.1.1071

Hypothesis: A New Role for the Renin-Angiotensin System in Ureteric Bud Branching

Ihor V Yosypiv ✉
PMCID: PMC2633671  PMID: 19521557

Abstract

Branching morphogenesis in the developing mammalian kidney involves growth and branching of the ureteric bud (UB), leading to formation of its daughter collecting ducts, calyces, pelvis and ureters. Even subtle defects in the efficiency and/or accuracy of this process have profound effects on the ultimate development of the kidney and result in congenital abnormalities of the kidney and urinary tract. This review summarizes current knowledge regarding a number of genes known to regulate UB development and emphasizes an emerging role for the renin-angiotensin system (RAS) in renal branching morphogenesis. Mutations in the genes encoding components of the RAS in mice cause renal papillary hypoplasia, hydronephrosis, and urinary concentrating defect. These findings imply that UB-derived epithelia are targets for angiotensin (ANG) II actions during metanephric kidney development. Here, it is proposed that papillary hypoplasia in RAS-deficient mice is secondary to an intrinsic defect in the development of the renal medulla. This hypothesis is based on the following observations: (a) UB and surrounding stroma express angiotensinogen (AGT) and ANG II AT1 receptors in vivo; (b) ANG II stimulates UB cell process extension, branching and cord formation in collagen gel cultures in vitro; and (c) AT1 blockade inhibits ANG II-induced UB cell branching. It is further postulated that ANG II is a novel stroma-derived factor involved in stroma/UB cross-talk which regulates UB branching morphogenesis.

Key Words: kidney development, branching morphogenesis, renin-angiotensin, stromal mesenchyme, ureteric bud

Introduction

Congenital abnormalities of the kidney and urinary tract (CAKUT) are the major cause of renal failure in childhood, accounting for up to 35–54% of end-stage renal disease in children less than 4 years of age.1 Evidence is emerging that many CAKUT have a genetic and hereditary basis. The inheritance pattern of some CAKUT (autosomal-dominant or recessive polycystic kidney disease) is well known. In other CAKUT (obstructive uropathy, vesico-ureteral reflux, kidney aplasia), the hereditary mechanisms remain yet to be determined. In this respect, recent discovery of a number of genes involved in coordination of nephrogenesis provided a further impulse to explore in depth the pathogenesis of the CAKUT.

Overview of Kidney Development

The development of the permanent or metanephric kidney begins when the nephric duct (ND) forms a caudal diverticulum, the ureteric bud (UB), on embryonic (E) day E10.5 in mice and fifth week of gestation in humans (Fig. 1). The UB originates via reciprocal inductive interactions with the mesenchyme.2 Signals from the mesenchyme induce the UB to emerge from the ND, elongate, invade the mesenchyme and then grow and branch repeatedly by a process referred to as branching morphogenesis. Iterations of dichotomous branching of the UB tips doubles the number of branches with each of approximately 15 branching events in humans.3 This allows the UB to form its daughter collecting ducts, which subsequently undergo patterning to form the renal medulla, pelvis and the ureter.

Figure 1.

Figure 1

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Schematic representation of factors involved in kidney development. Lim1, WT1 and Pax2 are transcription factors that play a role in the development of pronephros, mesonephros and nephric duct (ND). Ureteric bud (UB) originates from the ND (on E10.5 in mice) in response to mesenchymal signaling and due to its intrinsic developmental program. UB induces mesenchyme to undergo patterning into two compartments: metanephrogenic (MM) and stromal (SM). MM, SM and UB interact reciprocally via the release of soluble growth factors to induce further UB branching morphogenesis and mesenchymal-to-epithelial transformation of the MM. MM forms nephron structures proximal to collecting ducts. UB gives rise to renal collecting ducts, calyces, pelvis and ureters. SM does not give rise to MM- or UB-derived structures, but regulates their development. Names of compartment-specific factors regulating metanephrogenesis are shown below respective compartments expressing them.

Each UB tip is capable of inducing the adjacent metanephrogenic mesenchyme (MM) to undergo mesenchymal-to-epithelial transition (MET) and form the glomerulus, proximal and distal tubules.4 Thus, UB branching morphogenesis is critical in determining total collecting duct and nephron number. Even subtle defects in the efficiency and/or accuracy of this process have profound effects on the ultimate development of the kidney and appearance of CAKUT.

In addition to its effects on MET of the MM, the UB induces the mesenchyme to undergo transformation into stromal mesenchyme (SM).5 Most recent data indicate that SM plays a key role in kidney development and is required for UB branching morphogenesis as well as for MET.6 To this end, available evidence supports the hypothesis that reciprocal cell signaling among the UB, the MM and the SM coordinates kidney development.

Genetic Control of Kidney Development

A number of diverse signaling molecules (transcription factors, growth factors, cell adhesion molecules, proteinases and others) have been shown to play a role in kidney development (Fig. 1). Many of these factors are specifically induced or downregulated to exert their actions in a temporally- and spatially-restricted manner. These coordinated sequential interactions act to orchestrate proper kidney development. Any aberrant alteration in these schemes may potentially lead to the development of CAKUT. The type of specific CAKUT will depend on the type of factor altered, timing of specific insult and ability of other factors to compensate for its pathologic change.

Transcription factors (TF) Lim-1 and Pax2 act earliest in development of the kidney. Both Lim-1 and Pax2 are necessary for proper induction of the ND. Genetic inactivation of Lim-1 or Pax2 in mice results in complete absence of the metanephros.7,8 GDNF, c-Ret, Eya1 and WT1 act immediately after or concurrently with Lim-1 and Pax2 during the first critical steps in metanephric development- outgrowth of the UB from the ND. Respective homozygous mutations of GDNF, c-Ret, Eya1 or WT1 in mice lead to a failure of UB outgrowth and resultant renal agenesis.9–15 Similar mechanisms account for abnormalities observed in Sall1, Emx2, limb-deformity or integrin α8 mutations. Here, UB is formed but fails to invade the mesenchyme or the invasion is delayed.16–19 This leads to a spectrum of abnormalities ranging from kidney hypoplasia/dysplasia to aplasia.

Following induction of the UB, the next step in metanephrogenesis involves branching morphogenesis, MET and tubulogenesis. These processes are coordinated by a multitude of genes and their products. Wingless (Wnt) family members 2b, 4, 7b and 11 interact with the frizzled family of receptors and play an important role in kidney development. Wnt-2b is present in the SM and has been shown to induce UB growth and branching.20 Wnt 4 is detected on E11.5 in MM surrounding the tips of UB in mice.21 Later in development, Wnt 4 is present in epithelia of comma- and S-shaped bodies. Homozygous mutation of Wnt 4 culminates in kidneys with UBs but no nephrons.21 Therefore, Wnt 4 plays a critical role in MET. The critical role of bone morphogenic protein (BMP) 7 in renal development was demonstrated by the absence of MM, glomeruli, and a decreased number of UB branches and collecting ducts.22,23 Homeodomain-containing transcription factors, Hoxa11 and Hoxd11, are expressed exclusively in MM.24 An important role of Hoxa 11 and Hoxd 11 in branching morphogenesis has been suggested by reduced number of branch tips or complete absence of UB in double Hoxa11/Hoxd 11-deficient mice.

Secreted peptide growth factors represent yet another group of molecules that regulate UB and collecting duct branching. Genetic disruption of fibroblast growth factors (FGF) 7 or 10 leads to a decreased number of collecting ducts.25,26 Hepatocyte growth factor (HGF) is expressed in mesenchyme in apposition to UB branches and stimulates branching morphogenesis.27 Like HGF, epidermal growth factor (EGF) stimulates branching tubulogenesis in cultured cells in vitro,28 whereas transforming growth factor (TGF) β inhibits branching but not tubule elongation.29 Pleiotrophin is another MM-derived factor that has recently been shown to induce branching morphogenesis in the UBs.30

The factors that act at later stages of metanephrogenesis and regulate medullary patterning, formation of the calyces, pelvis and ureters include Glypican (GPC) 3, BMP 4, FGF7 and 10, p57KIP2, and the renin-angiotensin system (RAS) genes. Even though mutations of these genes cause abnormalities in the development of the renal collecting system, the mechanisms involved differ. Gpc3 knockout mice exhibit enhanced UB cell proliferation and branching leading to medullary dysplasia secondary to overgrowth.31 In contrast, mutations of FGF7, FGF10, and p57KIP2 genes cause medullary hypoplasia by decreasing the number of medullary collecting ducts.25,26,32 In contrast, heterozygous deletion of BMP4 causes medullary dysgenesis via induction of ectopic budding.33

A Role for the Stromal Mesenchyme in Kidney Development

The stromal mesenchyme (SM) is a complex mixture of cell types that do not differentiate into nephrons or the UBs/collecting ducts. SM traditionally have been thought to have a general supportive role. Recent studies demonstrated that SM modulates glomerulogenesis, tubulogenesis and branching morphogenesis. A key role for the SM in kidney development was demonstrated by disrupted glomerulogenesis and collecting system formation in mice with genetic inactivation of the BF-2/Foxd1 gene.6 BF-2/Foxd1 mutant kidneys had a significantly reduced number of UB branches compared to wild-type embryos. The SM itself was not altered morphologically. This indicates that BF2/Foxd1 mutation causes a defect in the ability of the SM to produce factors that are required for UB branching morphogenesis and MET.

Other stromal factors known to regulate kidney development include FGF 7, BMP4, retinoic acid receptor (RAR) α and β 2, capsulin/epicardin/Tcf21 (Pod1) and Wnt2b. FGF7 is expressed in the SM and its receptor, KGF-R, in the UB and collecting ducts.34 Genetic inactivation of FGF7 in mice causes a decrease in the size of the UB compartment and in total kidney size.25 In addition, FGF7-mutant kidneys have fewer nephrons than wild-type kidneys.

BMP4, a member of the TGF-β superfamily, plays an essential role in kidney and urinary tract organogenesis. In mice, BMP4 mRNA is expressed weakly in the ND and the MM on E10.5. On E12.5, after the UB branched several times, BMP4 is expressed only in the SM.33 At E14.5, BMP4 continues to be present in the SM and appears in S-shaped bodies and prospective ureter. Heterozygous mutant BMP4 mice develop diverse kidney abnormalities such as hypoplastic-dysplastic kidneys, duplex kidneys with bifid ureters, and hydronephrosis.33 In addition, the length of the main UB trunk and of its first two branches is shorter on E11.5. In concert with these findings, BMP4-loaded beads have been shown to promote elongation of the buds and to inhibit ectopic budding from the UB stalk in metanephric kidney culture in mice. It is conceivable that BMP4 counteracts branching induced by the GDNF/c-Ret pathway. The presence of BMP4 in collecting ducts and the fact that it induces the expression of smooth muscle actin in peri-ureteric mesenchymal cells, suggests a role for BMP4 in collecting duct/ureter morphogenesis at later stages of kidney development.

Retinoic acid is a naturally occurring derivative of vitamin A, or retinol. It signals via nuclear RARs α and β2. In situ hybridization analysis in mice demonstrated that RARα mRNA is expressed in the UB, the SM and the MM. Unlike RARα, RARβ2 is localized exclusively in the SM.35 Combined genetic inactivation of both RARs α and β2 causes formation of smaller kidneys with reduced number of UB branches present at birth.35 Expression of c-Ret is remarkably decreased in the mutant UB. In contrast, expression of other UB markers, GDNFRα and Wnt-11 or mesenchymal markers, GDNF, Pax2, WT1 and BMP7, is not affected by the absence of RARs α and β 2. Thus, retinoids are required for stromal, but not MM, patterning, and regulate UB branching via c-RET or other stromal factors. Genetic overexpression of c-RET in RAR α/β 2-deficient mice restored c-RET expression in the UB, and rescued stromal cell patterning and UB branching.36 Therefore, not only stroma-derived signals regulate UB morphogenesis, but c-Ret-dependent secreted UB signals regulate stromal cell patterning. In addition, RAR α/β 2 and c-RET are important in controlling maturation of the ureter. Specifically, spatially-correct insertion of the distal ureter into the bladder is dependent on retinoid-induced formation of the trigonal wedge.37 Pod1 (capsulin/epicardin/Tcf21) is a basic helix-loop- helix transcription factor that regulates UB branching morphogenesis. Genetic inactivation of Pod1 in mice causes major defects in UB branching and arrests glomerular development at capillary loop stage.38 The number of UB branches is decreased and a defect in branch pattern is observed in Pod1-null metanephroi: UB branches are crowded together and are present ectopically in the medulla. In addition, absence of Pod1 leads to ectopic expression of c-RET in the UB on E13.5. Like in RAR α/β 2-null mice, c-RET expression in Pod1 mutant kidneys is not restricted to UB tips at the periphery, but is seen in UB tips in the medulla and extends along the UB branches. In contrast, Foxd1/BF2 expression is not altered in Pod1 mutant kidneys, suggesting that Pod1 acts downstream of Foxd1/BF2.

The important role of stromal Pod1 in nephrogenesis has been recently demonstrated in chimeric Pod1-null/wild-type GFP mice.39 This study showed that the medulla in these mice is formed only from wild-type cells. This indicates that wild-type stromal cells can rescue the development of medulla in Pod1-null/wild-type GFP mice. In contrast, Pod1-expressing cells can differentiate into glomeruli and podocytes in chimeric mice. This suggests that presence of Pod1 in the SM is critical for the proper UB and glomerular development. The factors that are regulated by Pod1 in the stromal cell lineages are currently unknown.

Wnt-2b is the only member of the Wnt family present exclusively in the metanephric SM. Wnt-2b is weakly expressed in BF2/Foxd1-positive perinephric mesenchymal cells close to the stalk of the ureteric bud on E11.5 in mice by whole-mount in situ hybridization.20 Incubation of isolated UBs on NIH 3T3 cells expressing Wnt-2b causes an increase in the surface area of the UBs and in the number of branching tips, compared to control NIH 3T3 cells. Thus, stroma-located Wnt-2b and its signaling is capable of inducing UB growth and branching morphogenesis.

Human Syndromes Associated with CAKUT

A number of CAKUT associated with human syndromes result from aberrant nephrogenesis (Table 1). Branchio-Oto-Renal (BOR) syndrome is due to mutation of TF Eya1 and is characterized by the presence of cervical fistulas or cysts, preauricular pits, hearing loss and CAKUT.15,40 A spectrum of CAKUT observed in BOR is caused by defective UB outgrowth and branching morphogenesis. Pax2 mutation accounts for the Renal-Coloboma syndrome (RCS).41 RCS is associated with retinal coloboma, hearing loss and CAKUT. Renal defects in RCS are due to UB outgrowth/branching abnormalities.8 Kallman syndrome is characterized by hypogonadotropic gonadism and anosmia.42 A variety of CAKUT, including renal agenesis, duplex collecting systems, cystic dysplasia point to aberrant nephrogenesis. Maturity-onset diabetes of the young (MODY) is due to mutation of the hepatocyte nuclear factor (HNF) 1β.43 Besides diabetes mellitus, MODY is accompanied by multiple CAKUT such as medullary dysplasia, renal agenesis and others. Sall1 mutations cause Townes-Brocks syndrome (TBS).44 TBS is characterized by ear, anal and limb malformations as well as such CAKUT as renal hypoplasia, dysplasia and vesico-ureteral reflux (VUR). Simpson-Golabi-Behmel (SGB) syndrome, caused by mutations of heparin sulfate proteoglycan GPC3, leads to dysplastic renal medulla secondary to increased proliferation of UB-derived structures.45 Beckwith-Wiedemann syndrome is due to mutation in cell cycle regulatory gene p57KIP2 (BWS).32 BWS is an overgrowth syndrome sharing many features with SGB syndrome. Renal features include nephromegaly, cystic dysplasia, hydronephrosis and duplex collecting systems.46 Identification of the association of these nephrogenesis-controlling genes with syndromic CAKUT provides an impulse to further explore the evidence for a genetic basis of nonsyndromic CAKUT.

Table 1.

Hereditary Human Syndromes Associated with CAKUT

Syndrome (Reference) Inheritance Gene Renal phenotype Extrarenal phenotype
Branchio-Oto-Renal (45, 46) AD Eya1 Renal agenesis, UPJ, VUR, MDK, duplex ureter Preauricular pits, lateral cervical sinuses, cysts, fistulas, hearing loss
Renal-Coloboma (11, 47) AD Pax2 Renal hypoplasia, renal failure, VUR Optic disc coloboma, pits, dysplazia, hearing loss
Kallman (48) Sporadic, XL, AD, AR Kal Renal agenesis, VUR, MDK, duplex kidney, hydronephrosis Hypogonadotropic hypogonadism, anosmia
MODY (49) AD HNF1β Renal agenesis, cystic dysplasia dysplastic papilla Diabetes mellitus, genital tract anomalies
Townes-Brocks (50) AD Sall1 Renal hypoplasia, dysplasia, VUR Ear, anal, limb malformations
Simpson-Golabi-Behmel (51) XL GPC3 Medulllary dysplasia Macrosomia, macroglossia, omphalocele accessory nipples
Beckwith-Wiedemann (35, 52) AD p57KIP2 Nephromegaly, simple cysts, medullary cysts hydronephrosis, duplex collecting systems Macrosomia, macroglossia, abdominal wall defects, earlobe fissures, hypoglycemia
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Human syndromes associated with mutations of genes involved in kidney development. AD, autosomal-dominant; AR, autosomal-recessive; XL, Xlinked; UPJ, uretero-pelvic junction obstruction; VUR, vesico-ureteral reflux; MDK, multicystic-dysplastic kidney.

The Renin-Angiotensin System

In the renin-angiotensin system (RAS), renin cleaves angiotensinogen (AGT) to generate angiotensin (ANG) I. This is followed by the conversion of ANG I to ANG II by angiotensin-converting enzyme (ACE). ANG II is the principal effector peptide hormone which acts via two major types of receptors: AT1 and AT2. In the mature kidney, most of the physiological effects of ANG II are mediated by AT1. AT1 increases renal vascular resistance, tubular epithelial sodium reabsorption and glomerular filtration pressure.47,48 In addition, AT1 is a mitogen for renal vascular and mesangial cells.49 In contrast, AT2 causes bradykinin/NO-mediated dilation of the afferent arteriole, increases renal sodium excretion and inhibits cell growth and proliferation in mesangial cells.50–52 Thus, AT2 counteracts the vasoconstrictor, salt-retaining and proliferative effects of AT1.

Role of the Renin-Angiotensin System in Kidney Development

Pharmacological and gene targeting studies have clearly demonstrated that the renin-angiotensin system (RAS) plays an essential role during nephrogenesis.53–56 The developing kidney expresses all the components of the RAS.57–59 The activity of the renal RAS is high during fetal and neonatal life and declines during postnatal maturation. Renin mRNA levels and ANG II levels are 20- and 6-fold higher, respectively, in newborn than adult kidneys.57,60

AT1 and AT2 receptors are abundantly expressed in the nephrogenic zone.61 However, the ontogenic expression of AT1 and AT2 receptors in the kidney differs: AT2 receptors are expressed earlier than AT1 receptors, peak during fetal metanephrogenesis and rapidly decline postnatally.61 AT1 receptor expression increases during gestation, peaks perinatally and declines gradually thereafter.61 The spatial distribution of the AT1 and AT2 receptor mRNA during ontogeny is also contrasting. AT1 mRNA is present in mature and maturing glomeruli, and in distal and proximal tubules. AT2 mRNA is present in mesenchymal cells adjacent to the stalk of the ureteric bud. In addition, AT1 receptor protein is expressed in the UB and its derivatives of the rat metanephros.62 Thus, AT1 expression appears to correlate with the differentiation and proliferation of glomerular and tubular cells and AT2—with the mesenchymal-epithelial interactions.

Recent studies by several groups have demonstrated that inactivation of the genes encoding components of the RAS in mice causes papillary hypoplasia, hydronephrosis and urinary concentrating defect.54–56 These findings imply that UB-derived epithelia are targets for ANG II actions during renal development. A role for the RAS in ureteric bud/collecting system development is likely because: (a) The developing kidney expresses all the components of the RAS57–59 and ANG II synthesis and AT1/AT2 receptor expression are enhanced during metanephrogenesis,60,61 and (b) Genetic studies have shown that inactivation of the AGT, ACE or AT1 genes causes abnormalities in the development of the renal medulla.54–56 AGT, ACE or AT1 mutant mice exhibit thinning of the medulla, atrophy of the papilla and dilation of the pelvis. These changes are most pronounced postnatally after the formation of the renal papilla. In addition, ACE and AT1 null animals also have a reduced ability to concentrate urine.55,56

To examine the importance of the RAS in UB branching morphogenesis, we recently tested the hypothesis that ANG II, acting via AT1, stimulates UB branching morphogenesis in vitro. Using immunohistochemistry, we demonstrated that AGT and AT1 are expressed in both UBs and the SM as early as on embryonic (E) day 12 in the mouse (Fig. 2). The expression of AGT and AT1 in UB-derived epithelia and surrounding SM increased progressively from E12 to E16. Interestingly, AT1 immunoreactivity was present on both luminal and basolateral aspects of UB branches.63 In this regard, recent studies in renin knock-in reporter mice have demonstrated that juxta-glomerular renin-producing cells originate from the MM/SM on E11–E12, at a time when UB branching is just beginning.64 This raises the intriguing possibility that ANG II can be generated locally in the SM and then act in a paracrine fashion on the adjacent AT1-expressing UBs to induce branching. Similarly, AT1 present in the SM may be important in mediating stromal ANG II signaling to stimulate UB branching. One possible pathway may involve ANG II-induced stimulation of stromal factor FGF7 and its coupling with FGF7 receptor expressed on the UB.25,65 This possibility is supported by the ability of ANG II to increase bFGF mRNA levels in luteal cells.66

Figure 2.

Figure 2

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Immunolocalization of ANG II AT1 (A, B) and AT2 (C) receptor proteins, and angiotensinogen (AGT) protein (D) in the fetal mouse kidney. (A) On E16, AT1 is expressed in the stromal mesenchyme (S), proximal tubules (PT), followed by ureteric buds (UB). (B) On E14, AT1 is present on both luminal and basolateral aspects of the UB. (C) On E13, AT2 is present in UB branches. (D) On E15, AGT is present in the UBs and stromal mesenchyme. G- glomerulus. Adapted from ref. 63 (with permission from the American Physiological Society).

The direct role of ANG II and AT1 in UB branching morphogenesis was further tested in UB cells derived from E11.5 mouse ureteric buds.63 Utilization of UB cell culture model allows to avoid confounding influences of the mesenchyme, and may be more relevant to define the direct role of ANG II in UB development. Importantly, cultured UB cells maintain expression of AT1 mRNA and protein. ANG II (10−5 M) increased the number and complexity of branches in UB cells grown in collagen matrix gels. The observed ANG II-induced increase in UB cell branching was abrogated in the presence of AT1 antagonist, Candesartan (10−6 M). These findings demonstrate that ANG II stimulates branching of UB cells in vitro via activation of the AT1 receptor.

Our findings of AGT in the SM and of AT1 in the UBs during active UB branching in vivo, coupled with AT1-mediated increase in UB cell branching in vitro, provides further support for SM/UB cross-talk and suggest that AGT and ANG II may represent novel stromal factors that regulate UB branching morphogenesis (Fig. 3). In this regard, delineating the effects of the AT1 null mutation on expression of stromal factors necessary for UB branching (BF2/Foxd1, FGF7, Wnt2b and RAR) will be crucial to our understanding of the mechanisms governing the development of the renal medulla.

Figure 3.

Figure 3

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Schematic representation of the concept of stroma/ureteric bud (UB) module and its role in UB branching morphogenesis. Angiotensin (ANG) II is generated in stroma from angiotensinogen (AGT) by renin (see ref. 64) and acts on AT1 receptors located on basolateral aspects of the UB to induce branching. AGT and ANG II interact reciprocally with other stromal factors to regulate UB branching.

Since ANG II stimulates peristalsis of the ureter, it has been previously proposed that the hydronephrosis in AT1-deficient mice mimics functional urinary obstruction.67 Our data challenge the “obstruction hypothesis” and suggest that the hydronephrosis in RAS-deficient mice is secondary to intrinsic defect in UB branching and aberrant development of the renal medulla.

The role of AT2 in UB branching is unknown. Most recent studies indicate that AT2 counteracts the proliferative actions of AT1.68 Our preliminary data demonstrate that AT2 is expressed in UB branches during mouse nephrogenesis.69 AT2 mutant mice exhibit ectopic ureteral budding and duplicated collecting systems.70 This suggests that AT2 inhibits aberrant ureteral budding. It is conceivable that unopposed stimulation of AT2 in AT1 mutant mice may hinder UB branching. Therefore, the ultimate effect of Ang II on UB branching may depend on the balance between AT1- and AT2-mediated actions.

The signaling events linking AT1 to growth and differentiation of UB cells have not been defined. Several signaling pathways, including Ras/Raf/MEK/ERK/AP-1 and PI3K/Akt, had been shown to mediate the effects of AT1 on cell proliferation and hypertrophy in vascular smooth muscle cells, fibroblasts and renal mesangial cells.71–73 Thus, one of the possible mechanisms leading to increased UB cell proliferation, survival, and morphogenesis may involve AT1-mediated stimulation of Ras/Raf/MEK/ERK/AP-1 and PI3K/Akt pathways.

In addition to regulating UB development, putative paracrine distal nephron ANG II-generating/responsive system may have other functions. ANG II, acting via AT1, regulates urinary concentrating ability.55 In the adult animal, ANG II acts via basolateral AT1 to stimulate luminal alkalinization in rabbit cortical collecting duct.74 In rat collecting duct, ANG II regulates H+-ATPase and basolateral K channel activities.75,76

Acknowledgements

The author would like to thank Mercedes Schroeder for technical assistance and Dr. Samir El-Dahr for critical reading of the manuscript.

This work was supported by NIH COBRE Grant P-20 RR017659.

Footnotes

Previously published online as an Organogenesis E-publication: http://www.landesbioscience.com/journals/organogenesis/abstract.php?id=1071

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