title: Peroxisome proliferator-activated receptor beta/delta exerts a strong protection from ischemic acute renal failure.
abstract: Ischemic acute renal failure is characterized by damages to the proximal straight tubule in the outer medulla. Lesions include loss of polarity, shedding into the tubule lumen, and eventually necrotic or apoptotic death of epithelial cells. It was recently shown that peroxisome proliferator-activated receptor beta/delta (PPARbeta/delta) increases keratinocyte survival after an inflammatory reaction. Therefore, whether PPARbeta/delta could contribute also to the control of tubular epithelium death after renal ischemia/reperfusion was tested. It was found that PPARbeta/delta+/- and PPARbeta/delta-/- mutant mice exhibited much greater kidney dysfunction and injury than wild-type counterparts after a 30-min renal ischemia followed by a 36-h reperfusion. Conversely, wild-type mice that were given the specific PPARbeta/delta ligand L-165041 before renal ischemia were completely protected against renal dysfunction, as indicated by the lack of rise in serum creatinine and fractional excretion of Na+. This protective effect was accompanied by a significant reduction in medullary necrosis, apoptosis, and inflammation. On the basis of in vitro studies, PPARbeta/delta ligands seem to exert their role by activating the antiapoptotic Akt signaling pathway and, unexpectedly, by increasing the spreading of tubular epithelial cells, thus limiting potentially their shedding and anoikis. These results point to PPARbeta/delta as a remarkable new target for preconditioning strategies.
authors.affiliation: INSERM U489, Hôpital Tenon, 4 rue de la Chine, Paris, France 75020.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Letavernier
authors.forename: Joëlle
authors.initials: J
authors.lastname: Perez
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Joye
authors.forename: Agnès
authors.initials: A
authors.lastname: Bellocq
authors.forename: Bruno
authors.initials: B
authors.lastname: Fouqueray
authors.forename: Jean-Philippe
authors.initials: JP
authors.lastname: Haymann
authors.forename: Didier
authors.initials: D
authors.lastname: Heudes
authors.forename: Walter
authors.initials: W
authors.lastname: Wahli
authors.forename: Béatrice
authors.initials: B
authors.lastname: Desvergne
authors.forename: Laurent
authors.initials: L
authors.lastname: Baud
mesh_terms: D000085:Acetates / Q000494:pharmacology; D000818:Animals; D017209:Apoptosis; D015153:Blotting, Western; D002478:Cells, Cultured; D003404:Creatinine / Q000097:blood; D004305:Dose-Response Relationship, Drug; D004847:Epithelial Cells / Q000166:cytology; D006801:Humans; D020287:In Situ Nick-End Labeling; D007249:Inflammation; D007511:Ischemia; D015603:Keratinocytes / Q000378:metabolism; D007668:Kidney / Q000166:cytology* / Q000378:metabolism / Q000473:pathology; D007684:Kidney Tubules / Q000378:metabolism; D008024:Ligands; D008264:Macrophages / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008856:Microscopy, Fluorescence; D009336:Necrosis; D009504:Neutrophils / Q000473:pathology; D047494:PPAR delta / Q000096:biosynthesis / Q000502:physiology*; D048068:PPAR-beta / Q000096:biosynthesis / Q000502:physiology*; D009195:Peroxidase / Q000378:metabolism; D010636:Phenols / Q000494:pharmacology; D010641:Phenotype; D010642:Phenoxyacetates; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D051437:Renal Insufficiency / Q000473:pathology*; D015398:Signal Transduction; D012964:Sodium / Q000737:chemistry; D013997:Time Factors
chemical_list: C520164:4-(3-(2-propyl-3-hydroxy-4-acetyl)phenoxy)propyloxyphenoxy acetic acid; D000085:Acetates; D008024:Ligands; D047494:PPAR delta; D048068:PPAR-beta; D010636:Phenols; D010642:Phenoxyacetates; D012964:Sodium; D003404:Creatinine; D009195:Peroxidase; D051057:Proto-Oncogene Proteins c-akt