Collecting duct‐specific gene inactivation of αENaC in the mouse kidney does not attenuate rosiglitazone‐induced weight gain

Abstract

PPARγ agonists (thiazolidinediones) induce fluid retention and weight gain, but the involved mechanisms remain unclear; a role for activation of PPARγ and the epithelial sodium channel ENaC in the collecting duct has been proposed (PNAS 102:9406, 2005; Nat Med. 11:861, 2005). To further test this hypothesis, studies were performed in mice with and without conditional inactivation of αENaC (Scnn1a) in the collecting duct. Scnn1aloxlox mice (control) were crossed with a transgenic line expressing Cre recombinase driven by the Hoxb7 promoter, Scnn1aloxloxcre (JCI 112:554, 2003). As expected, rosiglitazone (320mg/kg diet) rapidly increased body wt (BW) in Scnn1aloxlox mice compared with vehicle‐treatment (ΔBW day 11: 4.5±0.8 vs. 1.1±0.6%, P<0.005) and lowered hematocrit (44±1 vs. 47±1, P<0.0005). In the αENaC collecting duct knockout mice, rosiglitazone still increased body weight (ΔBW: 7.3±0.9 vs. 0.9±0.7%, P<0.0005) and decreased hematocrit (42±2 vs. 47±1, P<0.05). Real‐time PCR in wild‐type mice revealed that rosiglitazone modestly lowered αENaC expression in kidney cortex (to 76±7%, P<0.05)(but not medulla) without affecting γENaC expression. The data argue against a significant role of ENaC activity in the collecting duct in rosiglitazone‐induced weight gain.