Gender-Dependent Phenotype in Polycystic Kidney Disease Is Determined by Differential Intracellular Ca2+ Signals

Abstract

Autosomal dominant polycystic kidney disease (ADPKD) is caused by loss of function of PKD1 (polycystin 1) or PKD2 (polycystin 2). The Ca2+-activated Cl− channel TMEM16A has a central role in ADPKD. Expression and function of TMEM16A is upregulated in ADPKD which causes enhanced intracellular Ca2+ 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 Ca2+ concentrations in primary renal epithelial cells isolated from Pkd1−/− males. The results suggest enhanced intracellular Ca2+ levels contributing to augmented cell proliferation and cyst development in male kidneys. Enhanced resting Ca2+ 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 Ca2+ 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 Ca2+ levels, leading to enhanced TMEM16A currents. Augmented Ca2+ signaling is possibly due to enhanced expression of Ca2+ transporting/regulating proteins.

Modulation of P2X 4 receptor activity by ivermectin and 5‐BDBD has no effect on the development of ARPKD in PCK rats

“…It was reported that PKD is more severe in males than in female PCK rats (Lager et al, 2001). Moreover, intracellular Ca 2+ signaling and ATP‐induced response are enhanced in male epithelial cells, further driving cell proliferation and cyst growth (Talbi et al, 2021). Thus in our case, the potential difference in treatment between males in females is doubtful, and we did not explore it in our study.…”

A Comparative Presentation of Mouse Models That Recapitulate Most Features of Alport Syndrome

“…Although sex bias in the severity and progression of the disease is expected for the two Col4a5 models due to their X-linked nature, such bias is not expected for the autosomal Co4a3- and Co4a4 -based models. However, the phenotype of another autosomal kidney disease, polycystic kidney disease, is presented in a sex-dependent manner, despite its autosomal nature [ 34 ]. In addition, sex and background-dependent differences in the composition of GBM, associated with albuminuria, are reported in healthy mice [ 31 ].…”

Recent advances in understanding ion transport mechanisms in polycystic kidney disease

“…Interestingly, gender-dependent differences were recently observed in intracellular Ca 2+ concentration ([Ca 2+ ] i ) in ADPKD epithelium. Specifically, higher basal and ATP-induced [Ca 2+ ] i levels were detected in primary renal epithelial cells isolated from male mice (vs female cells), which were hypothesized to result in the larger TMEM16A currents in males [ 126 ].…”