Cyclic AMP-mediated cyst expansion.
In polycystic kidney disease (PKD), intracellular cAMP promotes cyst enlargement by stimulating mural epithelial cell proliferation and transepithelial fluid secretion. The proliferative effect of cAMP in PKD is unique in that cAMP is anti-mitogenic in normal renal epithelial cells. This phenotypic difference in the proliferative response to cAMP appears to involve cross-talk between cAMP and Ca(2+) signaling to B-Raf, a kinase upstream of the MEK/ERK pathway. In normal cells, B-Raf is repressed by Akt (protein kinase B), a Ca(2+)-dependent kinase, preventing cAMP activation of ERK and cell proliferation. In PKD cells, disruption of intracellular Ca(2+) homeostasis due to mutations in the PKD genes relieves Akt inhibition of B-Raf, allowing cAMP stimulation of B-Raf, ERK and cell proliferation. Fluid secretion by cystic cells is driven by cAMP-dependent transepithelial Cl(-) secretion involving apical cystic fibrosis transmembrane conductance regulator (CFTR) Cl(-) channels. This review summarizes the current knowledge of cAMP-dependent cyst expansion, focusing on cell proliferation and Cl(-)-dependent fluid secretion, and discusses potential therapeutic approaches to inhibit renal cAMP production and its downstream effects on cyst enlargement. This article is part of a Special Issue entitled: Polycystic Kidney Disease.
Department of Internal Medicine, University of Kansas Medical Center, Kansas City, KS, USA. dwallace@kumc.edu
Darren P
DP
Wallace
D000818:Animals; D001127:Arginine Vasopressin / Q000502:physiology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D020013:Calcium Signaling; D049109:Cell Proliferation; D002712:Chlorides / Q000378:metabolism; D000242:Cyclic AMP / Q000502:physiology*; D006801:Humans; D007668:Kidney / Q000473:pathology / Q000503:physiopathology; D020935:MAP Kinase Signaling System; D008954:Models, Biological; D007690:Polycystic Kidney Diseases / Q000188:drug therapy / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology*; D015398:Signal Transduction
D002121:Calcium Channel Blockers; D002712:Chlorides; D001127:Arginine Vasopressin; D000242:Cyclic AMP