Interaction of PPARα With the Canonic Wnt Pathway in the Regulation of Renal Fibrosis

Abstract

Peroxisome proliferator–activated receptor-α (PPARα) displays renoprotective effects with an unclear mechanism. Aberrant activation of the canonical Wnt pathway plays a key role in renal fibrosis. Renal levels of PPARα were downregulated in both type 1 and type 2 diabetes models. The PPARα agonist fenofibrate and overexpression of PPARα both attenuated the expression of fibrotic factors, and suppressed high glucose–induced or Wnt3a-induced Wnt signaling in renal cells. Fenofibrate inhibited Wnt signaling in the kidney of diabetic rats. A more renal prominent activation of Wnt signaling was detected both in PPARα−/− mice with diabetes or obstructive nephropathy and in PPARα−/− tubular cells treated with Wnt3a. PPARα did not block the transcriptional activity of β-catenin induced by a constitutively active mutant of lipoprotein receptor–related protein 6 (LRP6) or β-catenin. LRP6 stability was decreased by overexpression of PPARα and increased in PPARα−/− tubular cells, suggesting that PPARα interacts with Wnt signaling at the Wnt coreceptor level. 4-Hydroxynonenal–induced reactive oxygen species production, which resulted in LRP6 stability, was suppressed by overexpression of PPARα and dramatically enhanced in PPARα−/− tubular cells. Diabetic PPARα−/− mice showed more prominent NADPH oxidase-4 overexpression compared with diabetic wild-type mice, suggesting that the inhibitory effect of PPARα on Wnt signaling may be ascribed to its antioxidant activity. These observations identified a novel interaction between PPARα and the Wnt pathway, which is responsible, at least partially, for the therapeutic effects of fenofibrate on diabetic nephropathy.