Activation of farnesoid X receptor inhibits TMEM16A-mediated chloride secretion in renal collecting duct cells and retards renal cyst progression

Abstract

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 that 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-deleted collecting duct cells (mIMCD3^pkd1-/- cells). In vivo experiments were performed in cystic polycystic kidney (PCK) rats. Treating collecting duct cells with FXR agonists (GW4064 and altenusin) decreased TMEM16A-mediated Cl^-secretion, an effect that required FXR activation. The inhibitory effect of FXR activation correlated with a reduction in TMEM16A protein levels. Decreased TMEM16A protein expression was associated with reduced Tmem16a mRNA expression and activation of lysosomal degradation pathways. GW4064 and altenusin retarded the enlargement of cysts derived from mIMCD3^pkd1-/- cells, an effect attenuated by FXR inhibition. In cystic PCK rats, treatment with altenusin at doses of 7.5 and 15 mg/kg body wt significantly reduced the cystic index, kidney weight, blood urea nitrogen, and serum creatinine levels compared with vehicle-treated rats. These effects correlated with decreased TMEM16A expression in cystic kidneys. In addition, altenusin exhibited anti-inflammatory properties by attenuating the levels of inflammatory cytokines. This study highlights the role of FXR in regulating TMEM16A and in attenuating renal cyst progression, positioning FXR as a promising target for PKD treatment.