Advances in the understanding of cystogenesis and availability of animal models orthologous to human autosomal dominant polycystic kidney disease (ADPKD) and recessive polycystic kidney disease (ARPKD) will likely facilitate the development of treatments for these diseases. Proteins mutated in ADPKD and ARPKD, as well as in several animal models, are localized to renal primary cilia. These are thought to have a sensory function and contribute to the regulation of the intracellular calcium ([Ca2+]i). It seems likely that the maintenance of a differentiated renal epithelial phenotype, characterized by controlled fluid secretion and cell proliferation, requires precise functional coordination of cAMP and Ras/Raf/MEK/ERK signaling by [Ca2+]i. [Ca2+]i alterations, linked to genetic defects causing polycystic kidney disease, may hinder negative feedback mechanisms that control cAMP and Ras/Raf/MEK/ERK signaling, and result in increased fluid secretion and cell proliferation. cAMP levels, Raf kinase activities and ERK phosphorylation are increased in polycystic kidneys. There is also evidence of abnormal cross-talk between cAMP and MAPK pathways, that can be reproduced in wild-type cells by altering [Ca2+]i. While cAMP inhibits Ras–Raf-1-stimulated phosphorylation of ERK in normal kidney cells, it markedly increases B-Raf kinase activity and ERK phosphorylation in polycystic kidney cells. Treatment strategies should probably be aimed at increasing [Ca2+]i, inhibiting Ras/Raf/MEK/ERK signaling or lowering cAMP in the distal nephron and collecting duct. Vasopressin is the major adenylyl cyclase agonist in the collecting duct principal cells via a V2 receptor. OPC31260, a V2 receptor antagonist, lowers renal cAMP and markedly inhibits cystogenesis in four animal models of polycystic kidney disease, three of which are orthologous to human diseases (PCK rat, ARPKD; pcy mouse, adolescent nephronophthisis; Pkd2WS25/– mouse, ADPKD). The renal selectivity and safety profile of this class of drugs make it an excellent candidate for clinical trials.

Igarashi P, Somlo S: Genetics and pathogenesis of polycystic kidney disease. J Am Soc Nephrol 2002;13:2384–2398.
Barr MM, Sternberg PW: A polycystic kidney-disease gene homologue required for male mating behaviour. Nature 1999;401:386–389.
Pazour GJ, Rosenbaum JL: Intraflagellar transport and cilia-dependent diseases. Trends Cell Biol 2002;12:551–555.
Guay-Woodford LM: Murine models of polycystic kidney disease: Molecular and therapeutic insights. Am J Physiol Renal Physiol 2003;285:F1034–F1049.
Lin F, Hiesberger T, Cordes K, Sinclair AM, Goldstein LS, Somlo S, Igarashi P: Kidney-specific inactivation of the KIF3A subunit of kinesin-II inhibits renal ciliogenesis and produces polycystic kidney disease. Proc Natl Acad Sci USA 2003;100:5286–5291.
Praetorius HA, Spring KR: Bending the MDCK cell primary cilium increases intracellular calcium. J Membr Biol 2001;184:71–79.
Nauli SM, Alenghat FJ, Luo Y, Williams E, Vassilev P, Li X, Elia AEH, Lu W, Brown EM, Quinn SJ, Ingber DE, Zhou J: Polycystins 1 and 2 mediate mechanosensation in the primary cilium of kidney cells. Nat Genet 2003;33:129–137.
Liu W, Xu S, Woda C, Kim P, Weinbaum S, Satlin LM: Effect of flow and stretch on the [Ca2+]i response of principal and intercalated cells in cortical collecting duct. Am J Physiol Renal Physiol 2003;285:F998–F1012.
Qian Q, Hunter LW, Li M, Marin-Padilla M, Prakash YS, Harris PC, Somlo S, Torres VE, Sieck GC: Pkd2 haploinsufficiency alters intracellular calcium in vascular smooth muscle cells. Hum Mol Genet 2003;12:1875–1880.
Gao Z, Joseph E, Ruden DM, Lu X: Drosophila Pkd2 is haploid insufficient for mediating optimal smooth muscle contractility. J Biol Chem 2004 online.
Cullen PJ, Lockyer PJ: Integration of calcium and Ras signalling. Nat Rev Mol Cell Biol 2002;3:339–348.
Walker SA, Cullen PJ, Taylor JA, Lockyer PJ: Control of Ras cycling by Ca2+. FEBS Lett 2003;546:6–10.
Medema JP, Sark MW, Backendorf C, Bos JL: Calcium inhibits epidermal growth factor-induced activation of p21ras in human primary keratinocytes. Mol Cell Biol 1994;14:7078–7085.
Stork PJ, Schmitt JM: Crosstalk between cAMP and MAP kinase signaling in the regulation of cell proliferation. Trends Cell Biol 2002;12:258–266.
Peyssonnaux C, Eychene A: The Raf/MEK/ERK pathway: New concepts of activation. Biol Cell 2001;93:53–62.
Qiu W, Zhuang S, von Lintig FC, Boss GR, Pilz RB: Cell type-specific regulation of B-Raf kinase by cAMP and 14-3-3 proteins. J Biol Chem 2000;275:31921–31929.
Light Y, Paterson H, Marais R: 14-3-3 antagonizes Ras-mediated Raf-1 recruitment to the plasma membrane to maintain signaling fidelity. Mol Cell Biol 2002;22:4984–4996.
Chabardes D, Imbert-Teboul M, Elalouf JM: Functional properties of Ca2+-inhibitable type 5 and type 6 adenylyl cyclases and role of Ca2+ increase in the inhibition of intracellular cAMP content. Cell Signal 1999;11:651–663.
Chiono M, Mahey R, Tate G, Cooper DM: Capacitative Ca2+ entry exclusively inhibits cAMP synthesis in C6–2B glioma cells. Evidence that physiologically evoked Ca2+ entry regulates Ca2+-inhibitable adenylyl cyclase in non-excitable cells. J Biol Chem 1995;270:1149–1155.
Dousa TP: Cyclic-3′,5′-nucleotide phosphodiesterase isozymes in cell biology and pathophysiology of the kidney. Kidney Int 1999;55:29–62.
Gattone VH, Wang X, Harris PC, Torres VE: Inhibition of renal cystic disease development and progression by a vasopressin V2 receptor antagonist. Nat Med 2003;9:1323–1326.
Torres VE, Wang X, Qian Q, Somlo S, Harris PC, Gattone VH: Effective treatment of an orthologous model of autosomal dominant polycystic kidney disease. Nat Med 2004;10:363–364.
Yasuda G, Jeffries WB: Regulation of cAMP production in initial and terminal inner medullary collecting ducts. Kidney Int 1998;54:80–86.
Yip KP: Coupling of vasopressin-induced intracellular Ca2+ mobilization and apical exocytosis in perfused rat kidney collecting duct. J Physiol 2002;538:891–899.
Yamaguchi T, Nagao S, Wallace DP, Belibi FA, Cowley BD, Pelling JC, Grantham JJ: Cyclic AMP activates B-Raf and ERK in cyst epithelial cells from autosomal-dominant polycystic kidneys. Kidney Int 2003;63:1983–1994.
Wallace DP, Christensen M, Reif G, Belibi F, Thrasher B, Herrell D, Grantham JJ: Electrolyte and fluid secretion by cultured human inner medullary collecting duct cells. Am J Physiol Renal Physiol 2002;283:F1337–F1350.
Torres VE, Sweeney WE, Jr., Wang X, Qian Q, Harris PC, Frost P, Avner ED: EGF receptor tyrosine kinase inhibition attenuates the development of PKD in Han:SPRD rats. Kidney Int 2003;64:1573–1579.
Gile R, Cowley B, Jr., Gattone V, II, O’Donnell M, Swan S, Grantham J: Effect of lovastatin on the development of polycystic kidney disease in the Han:SPRD rat. Am J Kid Dis 1995;26:501–507.
Muto S, Aiba A, Saito Y, Nakao K, Nakamura K, Tomita K, Kitamura T, Kurabayashi M, Nagai R, Higashihara E, Harris PC, Katsuki M, Horie S: Pioglitazone improves the phenotype and molecular defects of a targeted Pkd1 mutant. Hum Mol Genet 2002;11:1731–1742.
Chapman A, Guay-Woodford L, Grantham JJ, Torres V, Bae K, Baumgarten D, Kenney P, King B, Glockner J, Wetzel L, Brummer M, O’Neill C, Robbin M, Bennett W, Klahr S, Hirschman G, Kimmel P, Thompson P, Miller J: Renal structure in early autosomal dominant polycystic kidney disease (ADPKD); the Consortium for Radiologic Imaging Studies of Polycystic Kidney Disease (CRISP) Cohort. Kidney Int 2003;64:1035–1045.
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