Gender-Dependent Phenotype in Polycystic Kidney Disease Is Determined by Differential Intracellular Ca(2+) Signals

Autosomal dominant polycystic kidney disease (ADPKD) is caused by loss of function of PKD1 (polycystin 1) or PKD2 (polycystin 2). The Ca(2+)-activated Cl(−) channel TMEM16A has a central role in ADPKD. Expression and function of TMEM16A is upregulated in ADPKD which causes enhanced intracellular Ca(2+) signaling, cell proliferation, and ion secretion. We analyzed kidneys from Pkd1 knockout mice and found a more pronounced phenotype in males compared to females, despite similar levels of expression for renal tubular TMEM16A. Cell proliferation, which is known to be enhanced with loss of Pkd1(−/−), was larger in male when compared to female Pkd1(−/−) cells. This was paralleled by higher basal intracellular Ca(2+) concentrations in primary renal epithelial cells isolated from Pkd1(−/−) males. The results suggest enhanced intracellular Ca(2+) levels contributing to augmented cell proliferation and cyst development in male kidneys. Enhanced resting Ca(2+) also caused larger basal chloride currents in male primary cells, as detected in patch clamp recordings. Incubation of mouse primary cells, mCCDcl1 collecting duct cells or M1 collecting duct cells with dihydrotestosterone (DHT) enhanced basal Ca(2+) levels and increased basal and ATP-stimulated TMEM16A chloride currents. Taken together, the more severe cystic phenotype in males is likely to be caused by enhanced cell proliferation, possibly due to enhanced basal and ATP-induced intracellular Ca(2+) levels, leading to enhanced TMEM16A currents. Augmented Ca(2+) signaling is possibly due to enhanced expression of Ca(2+) transporting/regulating proteins.