The farnesoid X receptor (FXR) plays a role in the regulation of renal transporters and ion channels. Our previous study reported that activation of FXR inhibited cystic fibrosis transmembrane conductance regulator (CFTR)-mediated Cl- secretion and retarded microcyst progression. The present study aims to investigate whether FXR regulates TMEM16A, a calcium-activated Cl- channel, which plays a major role in renal cyst progression in polycystic kidney disease (PKD). In vitro experiments were conducted to investigate the roles of FXR in TMEM16A-mediated Cl⁻ secretion and cyst progression using wild-type and pkd1-deleting collecting duct cells (mIMCD3pkd1-/-). In vivo experiments were performed in cystic PCK rats. Treating the collecting duct cells with FXR agonists (GW4064 and altenusin) decreased TMEM16A-mediated Cl-secretion, which required FXR activation. The inhibitory effect of FXR activation was correlated with the decreased TMEM16A protein level, without affecting mRNA expression. Decreasing TMEM16A expression was involved in the activation of lysosome-induced degradation processes. Altenusin and GW4064 retarded the enlargement of mIMCD3pkd1-/- cells-derived cysts, which was attenuated by FXR inhibition. In cystic PCK rats, treatment with altenusin at doses of 7.5 and 15 mg/kgBW significantly reduced the cystic index, kidney weight, blood urea nitrogen, and serum creatinine levels compared with vehicle-treated rats. These effects were correlated with a decrease in TMEM16A expression in cystic kidneys. In addition, altenusin exhibited anti-inflammatory properties by attenuating inflammatory markers IL-6, MCP-1, and TNF-α. This study highlights the role of FXR in the regulation of TMEM16A and attenuating renal cyst progression, positioning FXR as a promising target for PKD treatment.
Srimai et al. (Fri,) studied this question.