Peroxisome proliferator-activated receptor beta/delta exerts a strong protection from ischemic acute renal failure.
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.
Letavernier
Emmanuel
E
INSERM U489, Hôpital Tenon, 4 rue de la Chine, Paris, France 75020.
Perez
Joëlle
J
Joye
Elisabeth
E
Bellocq
Agnès
A
Fouqueray
Bruno
B
Haymann
Jean-Philippe
JP
Heudes
Didier
D
Wahli
Walter
W
Desvergne
Béatrice
B
Baud
Laurent
L
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
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