Collecting Duct-Specific Gene Inactivation Of Alpha Enac In The Mouse Kidney Does Not Attenuate Rosiglitazone-Induced Weight Gain

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. Scnn1a loxlox mice (control) were crossed with a transgenic line expressing Cre recombinase driven by the Hoxb7 promoter, Scnn1a loxloxcre ( JCI 112:554, 2003). As expected, rosiglitazone (320mg/kg diet) rapidly increased body wt (BW) in Scnn1a loxlox 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.