Aberrant activation of canonical Wnt signaling plays a key role in renal fibrosis. Peroxisome proliferator-activated receptor-α (PPARα) has shown renoprotective effects with an unclear mechanism. Renal levels of PPARα were down-regulated in both type 1 and type 2 diabetic models. The PPARα agonist fenofibrate and over-expression of PPARα both attenuated expression of fibrotic factors and suppressed Wnt signaling in renal cells and in the kidney of diabetic rats. PPARα ablation enhanced activation of Wnt signaling in the kidneys of mice with diabetes or with obstructive nephropathy and in PPARα-/- tubular cells. PPARα did not block Wnt reporter expression induced by a constitutively active mutant of LRP6 or β-catenin. LRP6 stability was decreased by over-expression of PPARα and increased by PPARα ablation, suggesting that PPARα regulates Wnt signaling at the Wnt co-receptor level. LRP6 stability was enhanced by ROS and PPARα ablation while being suppressed by over-expression of PPARα. Diabetic PPARα-/- mice showed more prominent NOX4 over-expression, compared with diabetic wild-type mice, suggesting that PPARα regulates Wnt signaling likely through its anti-oxidant 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.
- Received April 1, 2016.
- Accepted July 27, 2016.
- © 2016 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.