Ren, Qun

Cardiovascular complications are the leading cause of morbidity and mortality in autosomal dominant polycystic kidney disease. Pkd2 + /− vascular smooth muscle cells (VSMCs) have an abnormal phenotype and defective intracellular Ca 2+ ([Ca 2+ ] i ) regulation. We examined cAMP content in vascular smooth muscles from Pkd2 + /− mice because cAMP is elevated in cystic renal epithelial cells. We found cAMP concentration was significantly increased in Pkd2 + /− vessels compared with wild-type vessels. Furthermore, reducing the wild-type VSMC [Ca 2+ ] i by Verapamil or BAPTA-AM significantly increased cellular cAMP concentration (mainly by phosphodiesterase [PDE] inhibition), the rate of VSMC proliferation (determined by direct cell counting, 3 H-incorporation, FACS analysis of cells entering S phase, and quantitative Western PCNA and ERK1/2 analyses), and the rate of apoptosis (by Hoechst staining, FACS analysis of the Annexin-V positive cells, and quantitative Western Bax, cytochrome c , and activated caspase 9 and 3 analyses). The low [Ca 2+ ] i induced VSMC proliferation was independent of cAMP/B-Raf signaling, while that of apoptosis was promoted by cAMP. In summary, Pkd2 + /− VSMCs have elevated cAMP levels. This elevation can also be induced by reducing [Ca 2+ ] i in wild-type VSMCs. The [Ca 2+ ] i reduction and cAMP accumulation can cause an increase in both cellular proliferation and apoptosis, resembling Pkd mutant phenotype.