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

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 <i>Pkd1</i>-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 <i>Tmem16a</i> 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.<b>NEW & NOTEWORTHY</b> Activation of farnesoid X receptor (FXR) downregulates TMEM16A-mediated Cl^- secretion in renal collecting duct cells. FXR stimulation reduces cyst enlargement in <i>Pkd1</i>-deleted collecting duct cells and in PKD rats. The data support that FXR may be a candidate target for the treatment of autosomal dominant polycystic kidney disease.