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Diabetes. 2016 Dec;65(12):3730-3743. Epub 2016 Aug 19.

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

Cheng R1,2, Ding L1,2, He X1,2, Takahashi Y2,3, Ma JX4,2.

Author information

1
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
2
Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
3
Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
4
Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK jian-xing-ma@ouhsc.edu.

Abstract

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.

PMID:
27543085
PMCID:
PMC5127249
DOI:
10.2337/db16-0426
[Indexed for MEDLINE]
Free PMC Article

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