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

Peroxisome proliferator-activated receptor-alpha (PPAR alpha) displays renoprotective effects with an unclear mechanism. Aberrant activation of the canonical Wnt pathway plays a key role in renal fibrosis. Renal levels of PPAR alpha were downregulated in both type 1 and type 2 diabetes models. The PPAR alpha agonist fenofibrate and overexpression of PPAR alpha 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 PPAR alpha(-/-) mice with diabetes or obstructive nephropathy and in PPAR alpha(-/-) tubular cells treated with Wnt3a. PPAR alpha did not block the transcriptional activity of beta-catenin induced by a constitutively active mutant of lipoprotein receptor-related protein 6 (LRP6) or beta-catenin. LRP6 stability was decreased by overexpression of PPAR alpha and increased in PPAR alpha(-/-) tubular cells, suggesting that PPAR alpha 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 PPAR alpha and dramatically enhanced in PPAR alpha(-/-) tubular cells. Diabetic PPAR alpha(-/-) mice showed more prominent NADPH oxidase-4 overexpression compared with diabetic wild-type mice, suggesting that the inhibitory effect of PPAR on Wnt signaling may be ascribed to its antioxidant activity. These observations identified a novel interaction between PPAR alpha and the Wnt pathway, which is responsible, at least partially, for the therapeutic effects of fenofibrate on diabetic nephropathy.