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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.

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