| First Author | Cheng R | Year | 2016 |
| Journal | Diabetes | Volume | 65 |
| Issue | 12 | Pages | 3730-3743 |
| PubMed ID | 27543085 | Mgi Jnum | J:249450 |
| Mgi Id | MGI:5922121 | Doi | 10.2337/db16-0426 |
| Citation | Cheng R, et al. (2016) Interaction of PPARalpha With the Canonic Wnt Pathway in the Regulation of Renal Fibrosis. Diabetes 65(12):3730-3743 |
| abstractText | Peroxisome proliferator-activated receptor-alpha (PPARalpha) displays renoprotective effects with an unclear mechanism. Aberrant activation of the canonical Wnt pathway plays a key role in renal fibrosis. Renal levels of PPARalpha were downregulated in both type 1 and type 2 diabetes models. The PPARalpha agonist fenofibrate and overexpression of PPARalpha 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 PPARalpha-/- mice with diabetes or obstructive nephropathy and in PPARalpha-/- tubular cells treated with Wnt3a. PPARalpha 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 PPARalpha and increased in PPARalpha-/- tubular cells, suggesting that PPARalpha 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 PPARalpha and dramatically enhanced in PPARalpha-/- tubular cells. Diabetic PPARalpha-/- mice showed more prominent NADPH oxidase-4 overexpression compared with diabetic wild-type mice, suggesting that the inhibitory effect of PPARalpha on Wnt signaling may be ascribed to its antioxidant activity. These observations identified a novel interaction between PPARalpha and the Wnt pathway, which is responsible, at least partially, for the therapeutic effects of fenofibrate on diabetic nephropathy. |
