Pediatric Nephrology

, Volume 24, Issue 6, pp 1113–1120 | Cite as

Renin–angiotensin system–growth factor cross-talk: a novel mechanism for ureteric bud morphogenesis

Review
First Online:
Received:
Revised:
Accepted:

Abstract

The renin–angiotensin system (RAS) plays a critical role in kidney development. Mutations in the genes encoding components of the RAS cause a spectrum of congenital abnormalities of the kidney and renal collecting system, ranging from hypoplasia of the renal medulla and hydronephrosis in mice to renal tubular dysgenesis in humans. However, the mechanisms by which an intact RAS controls proper renal system development and how aberrations in the RAS result in abnormal kidney and renal collecting system development are poorly understood. The renal collecting system originates from the ureteric bud (UB). A number of transcription and growth factors regulate UB branching morphogenesis to ultimately form the ureter, pelvis, calyces, medullary, and cortical collecting ducts. Importantly, UB morphogenesis is a key developmental process that controls organogenesis of the entire metanephros. This review emphasizes emerging insights into the role for the RAS in UB morphogenesis and explores the mechanisms whereby RAS regulates this important process. A conceptual framework derived from recent work indicates that cooperation between the angiotensin II AT1 receptor and receptor tyrosine kinase signaling performs essential functions during renal collecting system development via control of UB branching morphogenesis.

Keywords

c-Ret Epidermal growth factor receptor GDNF Kidney development Renin–angiotensin Ureteric bud 
This is a preview of subscription content, log in to check access.

Notes

Acknowledgments

The author would like to thank colleagues who have contributed in various ways to our studies in this area, particularly Mercedes Schroeder, Mary Kate Boh, Melissa Spera, Renfang Song, and Samir El-Dahr. The original work was supported by NIH Grants P20 RR17659 and DK071699-01 (Ihor Yosypiv).

References

  1. 1.
    Yosypiv IV (2004) Hypothesis: a novel role for the renin-angiotensin system in ureteric bud branching. Organogenesis 1:26–32PubMedGoogle Scholar
  2. 2.
    Rossetti S, Harris PC (2007) Genotype-phenotype correlations in autosomal dominant and autosomal recessive polycystic kidney disease. J Am Soc Nephrol 18:1374–1380PubMedCrossRefGoogle Scholar
  3. 3.
    Nagata M, Tanimoto K, Fukamizu A, Kon Y, Sugiyama F, Yagami K, Murakami K, Watanabe T (1996) Nephrogenesis and renovascular development in angiotensinogen-deficient mice. Lab Invest 75:745–753PubMedGoogle Scholar
  4. 4.
    Niimura F, Labosky PA, Kakuchi J, Okubo S, Yoshida H, Oikawa T, Ichiki T, Naftilan AJ, Fogo A, Inagami T (1995) Gene targeting in mice reveals a requirement for angiotensin in the development and maintenance of kidney morphology and growth factor regulation. J Clin Invest 96:2947–2954PubMedCrossRefGoogle Scholar
  5. 5.
    Takahashi N, Lopez ML, Cowhig JE Jr, Taylor MA, Hatada T, Riggs E, Lee G, Gomez RA, Kim HS, Smithies O (2005) Ren1c homozygous null mice are hypotensive and polyuric, but heterozygotes are indistinguishable from wild-type. J Am Soc Nephrol 16:125–132PubMedCrossRefGoogle Scholar
  6. 6.
    Esther CR Jr, Howard TE, Marino EM, Goddard JM, Capecchi MR, Bernstein KE (1996) Mice lacking angiotensin-converting enzyme have low blood pressure, renal pathology, and reduced male fertility. Lab Invest 7:953–965Google Scholar
  7. 7.
    Oliverio MI, Kim HS, Ito M, Le T, Audoly L, Best CF, Hiller S, Kluckman K, Maeda N, Smithies O, Coffman TM (1998) Reduced growth, abnormal kidney structure, and type 2 (AT2) angiotensin receptor-mediated blood pressure regulation in mice lacking both AT1A and AT1B receptors for angiotensin II. Proc Natl Acad Sci USA 95:15496–15501PubMedCrossRefGoogle Scholar
  8. 8.
    Tsuchida S, Matsusaka T, Chen X, Okubo S, Niimura F, Nishimura H, Fogo A, Utsunomiya H, Inagami T, Ichikawa I (1998) Murine double nullizygotes of the angiotensin type 1A and 1B receptor genes duplicate severe abnormal phenotypes of angiotensinogen nullizygotes. J Clin Invest 101:755–760PubMedCrossRefGoogle Scholar
  9. 9.
    Miyazaki Y, Tsuchida S, Fogo A, Ichikawa I (1999) The renal lesions that develop in neonatal mice during angiotensin inhibition mimic obstructive nephropathy. Kidney Int 55:1683–1695PubMedCrossRefGoogle Scholar
  10. 10.
    Gribouval O, Gonzales M, Neuhaus T (2005) Mutations in genes in the renin-angiotensin system are associated with autosomal recessive renal tubular dysgenesis. Nat Genet 37:964–968PubMedCrossRefGoogle Scholar
  11. 11.
    North American Pediatric Renal Trials and Collaborative Studies (2006) Annual report. NAPRTCS, BostonGoogle Scholar
  12. 12.
    Saxen L (1987) Organogenesis of the kidney. Cambridge University Press, CambridgeGoogle Scholar
  13. 13.
    Ekblom P (1989) Developmentally regulated conversion of mesenchyme to epithelium. FASEB J 3:2141–2150PubMedGoogle Scholar
  14. 14.
    Grobstein C (1953) Inductive epithelio-mesenchymal interaction in cultured organ rudiments of the mouse metanephros. Science 118:52–55PubMedCrossRefGoogle Scholar
  15. 15.
    Batourina E, Choi C, Paragas N, Bello N, Hensle T, Costantini FD, Schuchardt A, Bacallao RL, Mendelsohn CL (2002) Distal ureter morphogenesis depends on epithelial cell remodeling mediated by vitamin A and Ret. Nat Genet 32:109–115PubMedCrossRefGoogle Scholar
  16. 16.
    Batourina E, Tsai S, Lambert S, Sprenkle P, Viana R, Dutta S, Hensle T, Wang F, Niederreither K, McMahon AP, Carroll TJ, Mendelsohn CL (2005) Apoptosis induced by vitamin A signaling is crucial for connecting the ureters to the bladder. Nat Genet 37:1082–1089PubMedCrossRefGoogle Scholar
  17. 17.
    Sakurai H, Nigam S (1998) In vitro branching tubulogenesis: implications for developmental and cystic disorders, nephron number, renal repair, and nephron engineering. Kidney Int 54:14–26PubMedCrossRefGoogle Scholar
  18. 18.
    Brenner BM, Garcia DL, Anderson S (1988) Glomeruli and blood pressure. Less of one, more the other? Am J Hypertens 1:335–347PubMedGoogle Scholar
  19. 19.
    Lisle SJ, Lewis RM, Petry CJ, Ozanne SE, Hales CN, Forhead AJ (2003) Effect of maternal iron restriction during pregnancy on renal morphology in the adult rat offspring. Br J Nutr 90:33–39PubMedCrossRefGoogle Scholar
  20. 20.
    Costantini F (2006) Renal branching morphogenesis: concepts, questions, and recent advances. Differentiation 74:402–421PubMedCrossRefGoogle Scholar
  21. 21.
    Pachnis V, Mankoo B, Costantini F (1993) Expression of the c-ret proto-oncogene during mouse embryogenesis. Development 119:1005–1017PubMedGoogle Scholar
  22. 22.
    Brophy PD, Ostrom L, Lang KM, Dressler GR (2001) Regulation of ureteric bud outgrowth by Pax2-dependent activation of the glial derived neurotrophic factor gene. Development 128:4747–4756PubMedGoogle Scholar
  23. 23.
    Clarke JC, Patel SR, Raymond RM Jr, Andrew S, Robinson BG, Dressler GR, Brophy PD (2006) Regulation of c-Ret in the developing kidney is responsive to Pax2 gene dosage. Hum Mol Genet 15:3420–3428PubMedCrossRefGoogle Scholar
  24. 24.
    Hatini A, Huh SO, Herzlinger D, Soares VC, Lai E (1996) Essential role of stromal mesenchyme in kidney morphogenesis revealed by targeted disruption of Winged Helix transcription factor BF-2. Genes Dev 10:1467–1478PubMedCrossRefGoogle Scholar
  25. 25.
    Mendelsohn C, Batourina E, Fung S, Gilbert T, Dodd J (1999) Stromal cells mediate retinoid-dependent functions essential for renal development. Development 126:1139–1148PubMedGoogle Scholar
  26. 26.
    Carroll TJ, Park JS, Hayashi S, Majumdar A, McMahon AP (2005) Wnt9b plays a central role in the regulation of mesenchymal to epithelial transitions underlying organogenesis of the mammalian urogenital system. Dev Cell 9:283–292PubMedCrossRefGoogle Scholar
  27. 27.
    Majumdar A, Vainio S, Kispert A, McMahon J, McMahon AP (2003) Wnt11 and Ret/Gdnf pathways cooperate in regulating ureteric branching during metanephric kidney development. Development 130:3175–3185PubMedCrossRefGoogle Scholar
  28. 28.
    Basson MA, Watson-Johnson J, Shakya R, Akbulut S, Hyink D, Costantini FD, Wilson PD, Mason IJ, Licht JD (2006) Branching morphogenesis of the ureteric epithelium during kidney development is coordinated by the opposing functions of GDNF and Sprouty1. Dev Biol 299:466–477PubMedCrossRefGoogle Scholar
  29. 29.
    Bridgewater D, Cox B, Cain J, Lau A, Athaide V, Gill PS, Kuure S, Sainio K, Rosenblum ND (2008) Canonical WNT/beta-catenin signaling is required for ureteric branching. Dev Biol 317:83–94PubMedCrossRefGoogle Scholar
  30. 30.
    Schmidt-Ott KM, Chen X, Paragas N, Levinson RS, Mendelsohn CL, Barasch J (2006) c-kit delineates a distinct domain of progenitors in the developing kidney. Dev Biol 299:238–249PubMedCrossRefGoogle Scholar
  31. 31.
    Gao X, Chen X, Taglienti M, Rumballe B, Little MH, Kreidberg JA (2005) Angioblast-mesenchyme induction of early kidney development is mediated by Wt1 and Vegfa. Development 132:5437–5449PubMedCrossRefGoogle Scholar
  32. 32.
    Qiao J, Uzzo R, Obara-Ishihara T, Degenstein L, Fuchs E, Herzlinger D (1999) FGF-7 modulates ureteric bud growth and nephron number in the developing kidney. Development 126:547–554PubMedGoogle Scholar
  33. 33.
    Sakurai H, Barros EJ, Tsukamoto T, Barasch J, Nigam SK (1997) An in vitro tubulogenesis system using cell lines derived from the embryonic kidney shows dependence on multiple soluble growth factors. Proc Natl Acad Sci USA 94:6279–6284PubMedCrossRefGoogle Scholar
  34. 34.
    Ohuchi H, Hori Y, Yamasaki M, Harada H, Sekine K, Kato S, Itoh N (2000) FGF10 acts as a major ligand for FGF receptor 2 IIIb in mouse multi-organ development. Biochem Biophys Res Commun 277:643–649PubMedCrossRefGoogle Scholar
  35. 35.
    Ritvos O, Tuuri T, Erämaa M, Sainio K, Hildén K, Saxén L, Gilbert SF (1995) Activin disrupts epithelial branching morphogenesis in developing glandular organs of the mouse. Mech Dev 50:229–245PubMedCrossRefGoogle Scholar
  36. 36.
    Sakurai H, Tsukamoto T, Kjelsberg CA, Cantley LG, Nigam SK (1997) Department EGF receptor ligands are a large fraction of in vitro branching morphogens secreted by embryonic kidney. Am J Physiol 273:F463–F472PubMedGoogle Scholar
  37. 37.
    Qiao J, Bush KT, Steer DL, Stuart RO, Sakurai H, Wachsman W, Nigam SK (2001) Multiple fibroblast growth factors support growth of the ureteric bud but have different effects on branching morphogenesis. Mech Dev 109:123–135PubMedCrossRefGoogle Scholar
  38. 38.
    Zhao H, Kegg H, Grady S, Truong HT, Robinson ML, Baum M, Bates CM (2004) Center role of fibroblast growth factor receptors 1 and 2 in the ureteric bud. Dev Biol 276:403–415PubMedCrossRefGoogle Scholar
  39. 39.
    Zhang X, Ibrahimi OA, Olsen SK, Umemori H, Mohammadi M, Ornitz DM (2006) Department receptor specificity of the fibroblast growth factor family. The complete mammalian FGF family. J Biol Chem 281:15694–15700PubMedCrossRefGoogle Scholar
  40. 40.
    Bernardini N, Bianchi F, Lupetti M, Dolfi A (1996) Immunohistochemical localization of the epidermal growth factor, transforming growth factor alpha, and their receptor in the human mesonephros and metanephros. Dev Dyn 206:231–238PubMedCrossRefGoogle Scholar
  41. 41.
    Sakurai H, Tsukamoto T, Kjelsberg CA, Cantley LG, Nigam SK (1997) EGF receptor ligands are a large fraction of in vitro branching morphogens secreted by embryonic kidney. Am J Physiol 273:F463–F472PubMedGoogle Scholar
  42. 42.
    Threadgill DW, Dlugosz AA, Hansen LA, Tennenbaum T, Lichti U, Yee D, LaMantia C, Mourton T, Herrup K, Harris RC (1995) Targeted disruption of mouse EGF receptor: effect of genetic background on mutant phenotype. Science 269:230–234PubMedCrossRefGoogle Scholar
  43. 43.
    Maeshima A, Vaughn DA, Choi Y, Nigam SK (2006) Activin A is an endogenous inhibitor of ureteric bud outgrowth from the Wolffian duct. Dev Biol 295:473–485PubMedCrossRefGoogle Scholar
  44. 44.
    Cain JE, Hartwig S, Bertram JF, Rosenblum ND (2008) Bone morphogenetic protein signaling in the developing kidney: present and future. Differentiation 76:831–842Google Scholar
  45. 45.
    Bush KT, Sakurai H, Steer DL, Leonard MO, Sampogna RV, Meyer TN, Schwesinger C, Qiao J, Nigam SK (2004) TGF-beta superfamily members modulate growth, branching, shaping, and patterning of the ureteric bud. Dev Biol 266:285–298PubMedCrossRefGoogle Scholar
  46. 46.
    Piscione TD, Yager TD, Gupta IR, Grinfeld B, Pei Y, Attisano L, Wrana JL, Rosenblum ND (1997) BMP-2 and OP-1 exert direct and opposite effects on renal branching morphogenesis. Am J Physiol 273:F961–F975PubMedGoogle Scholar
  47. 47.
    Miyazaki Y, Oshima K, Fogo A, Ichikawa I (2000) Bone morphogenetic protein 4 regulates the budding site and elongation of the mouse ureter. J Clin Invest 105:863–873PubMedCrossRefGoogle Scholar
  48. 48.
    Cain JE, Nion T, Jeulin D, Bertram JF (2005) BMP-4 amplifies asymmetric ureteric branching in the developing mouse kidney in vitro. Kidney Int 67:420–431PubMedCrossRefGoogle Scholar
  49. 49.
    Hartwig S, Bridgewater D, Di Giovanni V, Cain J, Mishina Y, Rosenblum ND (2008) BMP receptor ALK3 controls collecting system development. J Am Soc Nephrol 19:117–124PubMedCrossRefGoogle Scholar
  50. 50.
    Wolf G, Thaiss F, Schoeppe W, Stahl RA (1992) Angiotensin II-induced proliferation of cultured murine mesangial cells: inhibitory role of atrial natriuretic peptide. J Am Soc Nephrol 3:1270–1278PubMedGoogle Scholar
  51. 51.
    Goto M, Mukoyama M, Suga S, Matsumoto T, Nakagawa M, Ishibashi R, Kasahara M, Sugawara A, Tanaka I, Nakao K (1997) Growth-dependent induction of angiotensin II type 2 receptor in rat mesangial cells. Hypertension 30:358–362PubMedGoogle Scholar
  52. 52.
    Santos RA, Simoes e Silva AC, Maric C, Silva DM, Machado RP, de Buhr I, Heringer-Walther S, Pinheiro SV, Lopes MT, Bader M, Mendes EP, Lemos VS, Campagnole-Santos MJ, Schultheiss HP, Speth R, Walther T (2003) Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci USA 100:8258–8263PubMedCrossRefGoogle Scholar
  53. 53.
    Santos RA, Ferreira AJ (2007) Angiotensin-(1–7) and the renin-angiotensin system. Curr Opin Nephrol Hypertens 16:122–128PubMedCrossRefGoogle Scholar
  54. 54.
    Miyazaki Y, Tsuchida S, Nishimura H, Pope JC 4th, Harris RC, McKanna JM, Inagami T, Hogan BL, Fogo A, Ichikawa I (1998) Angiotensin induces the urinary peristaltic machinery during the perinatal period. J Clin Invest 102:1489–1497PubMedCrossRefGoogle Scholar
  55. 55.
    Schaefer C (2003) Angiotensin II-receptor-antagonists: further evidence of fetotoxicity but not teratogenicity. Birth Defects Res Part A Clin Mol Teratol 67:591–594PubMedCrossRefGoogle Scholar
  56. 56.
    Tabacova S, Little R, Tsong Y, Vega A, Kimmel CA (2003) Adverse pregnancy outcomes associated with maternal enalapril antihypertensive treatment. Pharmacoepidemiol Drug Saf 12:633–646PubMedCrossRefGoogle Scholar
  57. 57.
    Nishimura H, Yerkes E, Hohenfellner K, Miyazaki Y, Ma J, Hunley TE, Yoshida H, Ichiki T, Threadgill D, Phillips JA 3rd, Hogan BM, Fogo A, Brock JW 3rd, Inagami T, Ichikawa I (1999) Role of the angiotensin type 2 receptor gene in congenital anomalies of the kidney and urinary tract, CAKUT, of mice and men. Mol Cell 3:1–10PubMedCrossRefGoogle Scholar
  58. 58.
    Oshima K, Miyazaki Y, Brock JW, Adams MC, Ichikawa I, Pope JC (2001) Angiotensin type II receptor expression and ureteral budding. J Urol 166:1848–1852PubMedCrossRefGoogle Scholar
  59. 59.
    Zhang H, Wada J, Hida K, Tsuchiyama Y, Hiragushi K, Shikata K, Wang H, Lin S, Kanwar YS, Makino H (2001) Collectrin, a collecting duct-specific transmembrane glycoprotein, is a novel homolog of ACE2 and is developmentally regulated in embryonic kidneys. J Biol Chem 276:17132–17139PubMedCrossRefGoogle Scholar
  60. 60.
    Lacoste M, Cai Y, Guicharnaud L, Mounier F, Dumez Y, Bouvier R, Dijoud F, Gonzales M, Chatten J, Delezoide AL, Daniel L, Joubert M, Laurent N, Aziza J, Sellami T, Amar HB, Jarnet C, Frances AM, Daïkha-Dahmane F, Coulomb A, Neuhaus TJ, Foliguet B, Chenal P, Marcorelles P, Gasc JM, Corvol P, Gubler MC (2006) Renal tubular dysgenesis, a not uncommon autosomal recessive disorder leading to oligohydramnios: role of the renin-angiotensin system. J Am Soc Nephrol 17:2253–2263PubMedCrossRefGoogle Scholar
  61. 61.
    Iosipiv IV, Schroeder M (2003) A role for angiotensin II AT1 receptors in ureteric bud cell branching. Am J Physiol 285:F199–F207Google Scholar
  62. 62.
    Lopez ML, Pentz ES, Robert B, Abrahamson DR, Gomez RA (2001) Embryonic origin and lineage of juxtaglomerular cells. Am J Physiol 281:F345–F356Google Scholar
  63. 63.
    Yosypiv IV, Schroeder M, El-Dahr SS (2006) AT1R-EGFR crosstalk regulates ureteric bud branching morphogenesis. J Am Soc Nephrol 17:1005–1014PubMedCrossRefGoogle Scholar
  64. 64.
    Zhang SL, Moini B, Ingelfinger JR (2004) Angiotensin II increases Pax-2 expression in fetal kidney cells via the AT2 receptor. J Am Soc Nephrol 15:1452–1465PubMedCrossRefGoogle Scholar
  65. 65.
    Nilsson AB, Nitescu N, Chen Y, Guron GS, Marcussen N, Matejka GL, Friberg P (2000) IGF-I treatment attenuates renal abnormalities induced by neonatal ACE inhibition. Am J Physiol 279:R1050–R1060Google Scholar
  66. 66.
    Stirling D, Magness RR, Stone R, Waterman MR, Simpson ER (1990) Angiotensin II inhibits luteinizing hormone-stimulated cholesterol side chain cleavage expression and stimulates basic fibroblast growth factor expression in bovine luteal cells in primary culture. J Biol Chem 265:5–8PubMedGoogle Scholar
  67. 67.
    Yosypiv IV, Boh MK, Spera M, El-Dahr SS (2008) Downregulation of Spry-1, an inhibitor of GDNF/Ret, as a mechanism for angiotensin II-induced ureteric bud branching. Kidney Int doi: 10.1038/ki.2008.378
  68. 68.
    Tang MJ, Cai Y, Tsai SJ, Wang YK, Dressler GR (2002) Ureteric bud outgrowth in response to RET activation is mediated by phosphatidylinositol3-kinase. Dev Biol 243:128–136PubMedCrossRefGoogle Scholar
  69. 69.
    Kim D, Dressler GR (2007) PTEN modulates GDNF/RET mediated chemotaxis and branching morphogenesis in the developing kidney. Dev Biol 307:290–299PubMedCrossRefGoogle Scholar
  70. 70.
    Berry C, Touyz R, Dominiczak AF, Webb RC, Johns DG (2001) Angiotensin receptors: signaling,vascular pathophysiology, and interactions with ceramide. Am J Physiol 281:H2337–H2365Google Scholar
  71. 71.
    Watanabe G, Lee RJ, Albanese C, Rainey WE, Batle D, Pestell RG (1996) Angiotensin II activation of cyclin D1-dependent kinase activity. J Biol Chem 271:22570–22577PubMedCrossRefGoogle Scholar
  72. 72.
    Prenzel N, Zwick E, Daub H, Leserer M, Abraham R, Wallasch C, Ullrich A (1999) EGF receptor transactivation by G-protein-coupled receptors requires metalloproteinase cleavage of proHB-EGF. Nature 402:884–888PubMedGoogle Scholar
  73. 73.
    Ushio-Fukai M, Hilenski L, Santanam N, Becker PL, Ma Y, Griendling KK, Alexander RW (2001) Cholesterol depletion inhibits epidermal growth factor receptor transactivation by angiotensin II in vascular smooth muscle cells: role of cholesterol-rich microdomains and focal adhesions in angiotensin II signaling. J Biol Chem 276:48269–48275PubMedGoogle Scholar
  74. 74.
    Olivares-Reyes JA, Shah BH, Hernandez-Aranda J, Garcia-Gaballero A, Farshori MP, Gatcia-Sainz JA, Catt KJ (2005) Agonist-induced interactions between angiotensin AT1 and epidermal growth factor receptors. Mol Pharmacol 68:356–364PubMedGoogle Scholar
  75. 75.
    Stoll M, Steckelings UM, Paul M, Bottari SP, Metzger R, Unger T (1995) The angiotensin AT2-receptor mediates inhibition of cell proliferation in coronary endothelial cells. J Clin Invest 95:651–657PubMedCrossRefGoogle Scholar
  76. 76.
    AbdAlla S, Lother H, Abdel-tawab AM, Quitterer U (2001) The angiotensin II AT2 receptor is an AT1 receptor antagonist. J Biol Chem 276:39721–39726PubMedCrossRefGoogle Scholar
  77. 77.
    Garcia-Villalba P, Denkers ND, Wittwer CT, Wittwer CT, Hoff C, Nelson RD, Mauch TJ (2003) Real-time PCR quantification of AT1 and AT2 angiotensin receptor mRNA expression in the developing rat kidney. Nephron. Exp Nephrol 94:e154–e159CrossRefGoogle Scholar
  78. 78.
    Yosypiv IV (2004) A new role for the renin–angiotensin system in ureteric bud branching. Organogenesis 1:26–32PubMedCrossRefGoogle Scholar

Copyright information

© IPNA 2008

Authors and Affiliations

  1. 1.Section of Pediatric Nephrology, Department of Pediatrics, Hypertension and Renal Center of ExcellenceTulane University Health Sciences CenterNew OrleansUSA
  2. 2.Department of Pediatrics, SL-37Tulane University Health Sciences CenterNew OrleansUSA

Personalised recommendations