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 Ca2+ 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 Ca2+-dependent kinase, preventing cAMP activation of ERK and cell proliferation. In PKD cells, disruption of intracellular Ca2+ 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.

Research Highlights
► cAMP stimulates the proliferation of PKD cystic epithelial cells, but not normal renal cells, through activation of the ERK mitogen-activated protein kinase pathway.
► Aberrant intracellular calcium signaling and/or reduced steady-state calcium levels in PKD cells determine the mitogenic response to cAMP.
► cAMP stimulates solute and fluid secretion through activation of CFTR-dependent chloride secretion.
► Several approaches to reduce renal cAMP and inhibit cAMP-dependent cell proliferation and fluid secretion are being considered for the treatment of PKD.