title: Interaction of PPARα With the Canonic Wnt Pathway in the Regulation of Renal Fibrosis.
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.
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.|Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Rui
authors.initials: R
authors.lastname: Cheng
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.|Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Lexi
authors.initials: L
authors.lastname: Ding
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK.|Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Xuemin
authors.initials: X
authors.lastname: He
authors.affiliation: Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK.|Department of Medicine, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Takahashi
authors.affiliation: Department of Physiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK jian-xing-ma@ouhsc.edu.|Harold Hamm Diabetes Center, University of Oklahoma Health Sciences Center, Oklahoma City, OK.
authors.forename: Jian-Xing
authors.initials: JX
authors.lastname: Ma
mesh_terms: D000818:Animals; D015153:Blotting, Western; D002478:Cells, Cultured; D003928:Diabetic Nephropathies / Q000378:metabolism; D011345:Fenofibrate / Q000494:pharmacology; D005355:Fibrosis / Q000378:metabolism*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism; D007674:Kidney Diseases / Q000378:metabolism*; D007687:Kidney Tubules, Proximal / Q000378:metabolism; D060488:Low Density Lipoprotein Receptor-Related Protein-6 / Q000235:genetics / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D047493:PPAR alpha / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism; D060449:Wnt Signaling Pathway / Q000235:genetics / Q000502:physiology*; D051176:beta Catenin / Q000235:genetics / Q000378:metabolism
chemical_list: D060488:Low Density Lipoprotein Receptor-Related Protein-6; D047493:PPAR alpha; D017382:Reactive Oxygen Species; D051153:Wnt Proteins; D051176:beta Catenin; D011345:Fenofibrate