The role of the prorenin receptor (PRR) in the regulation of ureteric bud (UB) branching morphogenesis is unknown. Here, we investigated whether PRR acts specifically in the UB to regulate UB branching, kidney development and function. We demonstrate that embryonic (E) day E13.5 mouse metanephroi, isolated intact E11.5 UBs and cultured UB cells express PRR mRNA. To study its role in UB development, we conditionally ablated PRR in the developing UB (PRRUB？/？) using Hoxb7Cre mice. On E12.5, PRRUB？/？ mice had decreased UB branching and increased UB cell apoptosis. These defects were associated with decreased expression of Ret, Wnt11, Etv4/Etv5, and reduced phosphorylation of Erk1/2 in the UB. On E18.5, mutants had marked kidney hypoplasia, widespread apoptosis of medullary collecting duct cells and decreased expression of Foxi1, AE1 and H+-ATPase α4 mRNA. Ultimately, they developed occasional small cysts in medullary collecting ducts and had decreased nephron number. To test the functional consequences of these alterations, we determined the ability of PRRUB？/？ mice to acidify and concentrate the urine on postnatal (P) day P30. PRRUB？/？ mice were polyuric, had lower urine osmolality and a higher urine pH following 48 hours of acidic loading with NH4Cl. Taken together, these data show that PRR present in the UB epithelia performs essential functions during UB branching morphogenesis and collecting duct development via control of Ret/Wnt11 pathway gene expression, UB cell survival, activation of Erk1/2, terminal differentiation and function of collecting duct cells needed for maintaining adequate water and acid-base homeostasis. We propose that mutations in PRR could possibly cause renal hypodysplasia and renal tubular acidosis in humans.
References
[1]
North American Pediatric Trials and Collaborative Studies. NAPRTCS Annual report. (2010) https://web.emmes.com/study/ped/annlrept？/2010_Report.pdf.Accessed 2013 Jan 6.
[2]
Schedl A (2007) Renal abnormalities and their developmental origin. Nat Rev Genet 8: 791–802.
[3]
Song R, Yosypiv IV (2011) Genetics of Congenital Anomalies of the Kidney and Urinary Tract. Pediatric Nephrology 26: 353–364.
[4]
Costantini F, Kopan R (2010) Patterning a complex organ: branching morphogenesis and nephron segmentation in kidney development. Dev Cell 18: 698–712.
[5]
Al-Awqati Q, Gao XB (2011) Differentiation of intercalated cells in the kidney. Physiology (Bethesda) 26: 266–272.
[6]
Rojek A, Füchtbauer EM, Kwon TH, Fr？kiaer J, Nielsen S (2006) Severe urinary concentrating defect in renal collecting duct-selective AQP2 conditional-knockout mice. Proc Natl Acad Sci U S A 103: 6037–6042.
[7]
Jeong HW, Jeon US, Koo BK, Kim WY, Im SK, et al. (2009) Inactivation of Notch signaling in the renal collecting duct causes nephrogenic diabetes insipidus in mice. J Clin Invest 119: 3290–3300.
[8]
Blomqvist SR, Vidarsson H, Fitzgerald S, Johansson BR, Ollerstam A, et al. (2004) Distal renal tubular acidosis in mice that lack the forkhead transcription factor Foxi1. J Clin Invest 113: 1560–1570.
[9]
Nguyen G, Delarue F, Burcklé C, Bouzhir L, Giller T, et al. (2002) Pivotal role of the renin/prorenin receptor in angiotensin II production and cellular responses to renin. J Clin Invest 109: 1417–1427.
[10]
Kinouchi K, Ichihara A, Sano M, Sano M, Sun-Wada GH, et al. (2010) The (pro)renin receptor/ATP6AP2 is essential for vacuolar H+-ATPase assembly in murine cardiomyocytes. Circ Res 107: 30–34.
[11]
Cruciat CM, Ohkawara B, Acebron SP, Karaulanov E, Reinhard C, et al. (2010) Requirement of prorenin receptor and vacuolar H+-ATPase-mediated acidification for Wnt signaling. Science 327: 459–463.
[12]
Advani A, Kelly DJ, Cox AJ, White KE, Advani SL, et al. (2009) The (Pro)Renin Receptor Site-Specific and Functional Linkage to the Vacuolar H+-ATPase in the Kidney. Hypertension 54: 261–269.
[13]
Gonzalez AA, Lara LS, Luffman C, Seth DM, Prieto MC (2011) Soluble form of the (pro)renin receptor is augmented in the collecting duct and urine of chronic angiotensin II-dependent hypertensive rats. Hypertension 57: 859–864.
[14]
Inoue H, Noumi T, Nagata M, Murakami H, Kanazawa H (1999) Targeted disruption of the gene encoding the proteolipid subunit of mouse vacuolar H+-ATPase leads to early embryonic lethality. Biochim. Biophys 1413: 130–138.
[15]
Miura GI, Froelick GJ, Marsh DJ, Stark KL, Palmiter RD (2003) The d subunit of the vacuolar ATPase (Atp6d) is essential for embryonic development. Transgenic Res 12: 131–133.
[16]
Finberg KE, Wagner CA, Bailey MA, Paunescu TG, Breton S, et al. (2005) The B1-subunit of the H(+) ATPase is required for maximal urinary acidification. Proc Natl Acad Sci U S A 102: 13616–13621.
[17]
Fisher CE, Michael L, Barnett MW, Davies JA (2001) Erk MAP kinase regulates branching morphogenesis in the developing mouse kidney. Development 128: 4329–4338.
[18]
Zhao H, Kegg H, Grady S, Truong HT, Robinson ML, et al. (2004) Role of fibroblast growth factor receptors 1 and 2 in the ureteric bud. Dev Biol 276: 403–415.
[19]
Barasch J, Pressler L, Connor J, Malik A (1996) A ureteric bud cell line induces nephrogenesis in two steps by distinct signals. Am J Physiol 271: F50–F61.
[20]
Song R, Preston G, Yosypiv IV (2011) Angiotensin II stimulates in vitro branching morphogenesis of the isolated ureteric bud. Mechanisms of Development 128: 359–367.
[21]
Song R, Spera M, Garrett C, El-Dahr S, Yosypiv IV (2010) Angiotensin II AT2 Receptor Regulates Ureteric Bud Morphogenesis. American Journal of Physiology Renal Physiology 298: F807–F817.
[22]
Jouret F, Auzanneau C, Debaix H, Wada GH, Pretto C, et al. (2005) Ubiquitous and kidney-specific subunits of vacuolar H+-ATPase are differentially expressed during nephrogenesis. J Am Soc Nephrol 16: 3235–3246.
[23]
Nagalakshmi VK, Ren Q, Pugh MM, Valerius MT, McMahon AP, et al. (2011) Dicer regulates the development of nephrogenic and ureteric compartments in the mammalian kidney. Kidney Int 79: 317–330.
[24]
Yosypiv IV, Schroeder M, El-Dahr SS (2006) AT1R-EGFR crosstalk regulates ureteric bud branching morphogenesis. J Am Soc Nephrol 17: 1005–1014.
[25]
Huang Y, Wongamorntham S, Kasting J, McQuillan D, Owens RT, et al. (2006) Renin increases mesangial cell transforming growth factor-beta1 and matrix proteins through receptor-mediated, angiotensin II-independent mechanisms. Kidney Int 69: 105–113.
[26]
Buechling T, Bartscherer K, Ohkawara B, Chaudhary V, Spirohn K, et al. (2010) Wnt/Frizzled signaling requires dPRR, the Drosophila homolog of the prorenin receptor. Curr Biol 20: 1263–1268.
[27]
Karner CM, Chirumamilla R, Aoki S, Igarashi P, Wallingford JB, et al. (2009) Wnt9b signaling regulates planar cell polarity and kidney tubule morphogenesis. Nat Genet 41: 793–799.
[28]
Yu J, Carroll TJ, Rajagopal J, Kobayashi A, Ren Q, et al. (2009) A Wnt7b-dependent pathway regulates the orientation of epithelial cell division and establishes the cortico-medullary axis of the mammalian kidney. Development 136: 161–171.
[29]
Basson MA, Watson-Johnson J, Shakya R, Akbulut S, Hyink D, et al. (2006) Branching morphogenesis of the ureteric epithelium during kidney development is coordinated by the opposing functions of GDNF and Sprouty1. Dev Biol 299: 466–477.
[30]
Chi X, Michos O, Shakya R, Riccio P, Enomoto H, et al. (2009) Ret-dependent cell rearrangements in the Wolffian duct epithelium initiate ureteric bud morphogenesis. Dev Cell 17: 199–209.
[31]
Lu BC, Cebrian C, Chi X, Kuure S, Kuo R, et al. (2009) Etv4 and Etv5 are required downstream of GDNF and Ret for kidney branching morphogenesis. Nat Genet 41: 1295–1302.
[32]
Jain S, Knoten A, Hoshi M, Wang H, Vohra B, et al. (2010) Organotypic specificity of key RET adaptor-docking sites in the pathogenesis of neurocristopathies and renal malformations in mice. J Clin Invest 120: 778–790.
[33]
Jain S, Encinas M, Johnson EM Jr, Midbrandt J (2006) Critical and distinct roles for key RET tyrosine docking sites in renal development. Genes Dev 20: 321–333.
[34]
Cain JE, Di Giovanni V, Smeeton J, Rosenblum ND (2010) Genetics of renal hypoplasia. Insights into the mechanisms controlling nephron endowment. Pediatr Res 68: 91–98.
[35]
Wagner CA, Finberg KE, Breton S, Marshansky V, Brown D, et al. (2004) Renal vacuolar H+-ATPase. Physiol Rev 84: 1263–314.
[36]
Vidarsson H, Westergren R, Heglind M, Blomqvist SR, Breton S, et al. (2009) The forkhead transcription factor Foxi1 is a master regulator of vacuolar H-ATPase proton pump subunits in the inner ear, kidney and epididymis. PLoS One 4 e4471.
[37]
Stover EH, Borthwick KJ, Bavalia C, Eady N, Fritz DM, et al. (2002) Novel ATP6V1B1 and ATP6V0A4 mutations in autosomal recessive distal renal tubular acidosis with new evidence for hearing loss. J Med Genet 39: 796–803.
[38]
Karet FE (2002) Inherited distal renal tubular acidosis. J Am Soc Nephrol 13: 2178–2184.
[39]
Lin SH, Bichet DG, Sasaki S, Kuwahara M, Arthus MF, et al. (2002) Two novel aquaporin-2 mutations responsible for congenital nephrogenic diabetes insipidus in Chinese families. J Clin Endocrinol Metab 87: 2694–2700.
[40]
Oshima Y, Kinouchi K, Ichihara A, Sakoda M, Kurauchi-Mito A, et al. (2011) Prorenin receptor is essential for normal podocyte structure and function. J Am Soc Nephrol 22: 2203–2212.
[41]
Riediger F, Quack I, Qadri F, Hartleben B, Park JK, et al. (2011) Prorenin receptor is essential for podocyte autophagy and survival. J Am Soc Nephrol 22: 2193–2202.
