期刊
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
卷 1812, 期 10, 页码 1291-1300出版社
ELSEVIER SCIENCE BV
DOI: 10.1016/j.bbadis.2010.11.005
关键词
Polycystic kidney disease; cAMP; Calcium; Cell proliferation; MAP kinase; Fluid secretion
资金
- National Institutes of Health [R01DK081579, P50DK057301]
- PKD Foundation
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. (C) 2010 Elsevier B.V. All rights reserved.
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