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 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 high glucose- 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 transcriptional activity of β-catenin induced by a constitutively active mutant of LRP6 or β-catenin. LRP6 stability was decreased by over-expression of PPARα and increased in PPARα-/- tubular cells, suggesting that PPARα interacts with Wnt signaling at the Wnt co-receptor level. 4-Hydroxynonenal-induced ROS production, which resulted in LRP6 stability, was suppressed by over-expression of PPARα, and dramatically enhanced in PPARα-/- tubular cells, Diabetic PPARα-/- mice showed more prominent NOX4 over-expression, compared with diabetic wild-type mice, suggesting that inhibitory effect of PPARα on Wnt signaling may be ascribed to 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 August 31, 2016.
- © 2016 by the American Diabetes Association.