title: BML-111 Attenuates Renal Ischemia/Reperfusion Injury Via Peroxisome Proliferator-Activated Receptor-α-Regulated Heme Oxygenase-1.
abstract: We examine whether BML-111, a lipoxin receptor agonist, inhibits renal ischemia/reperfusion (I/R) injury, and whether peroxisome proliferator-activated receptor-α (PPARα) or heme oxygenase-1 (HO-1) is involved in protective effects of BML-111 on kidney against I/R injury. Rats subjected to renal I/R injury were treated with or without BML-111. Renal histological and immunohistochemical studies were performed. Expressions of phosphorylated p38 mitogen-activated protein kinase (pp38 MAPK), phosphorylated PPARα (pPPARα), and HO-1 were assessed in NRK-52E cells exposed to BML-111. The binding activity of PPARα to peroxisome proliferator-responsive element (PPRE) on HO-1 promoter in the cells was determined. BML-111 treatment resulted in a marked reduction in the severity of histological features of renal I/R injury, and attenuated the rise in renal myeloperoxidase and malondialdehyde, blood urea nitrogen and creatinine, urinary N-acetyl-β-glucosaminidase, and leucine aminopeptidase levels caused by I/R injury. BML-111 stimulated the renal expressions of pPPARα and HO-1, and cellular messenger RNA (mRNA) and protein expressions of pPPARα and HO-1 which were both blocked by GW6471, a selective PPARα antagonist, and ZnPP-IX, a specific inhibitor of HO-1 pretreatment. The pp38 MAPK inhibitor SB203580 blocked the BML-111-induced expressions of pp38 MAPK, pPPARα, and HO-1 in NRK-52E cells. The binding activity of PPARα to PPRE in nuclear extracts of NRK-52E cells was enhanced by treatment of the cells with BML-111, and was suppressed by GW6471 and SB203580. BML-111 protects the kidney against I/R injury via activation of p38 MAPK/PPARα/HO-1 pathway.
authors.affiliation: Department of Pediatrics, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China. kad-yc@163.com.
authors.forename: Sheng-Hua
authors.initials: SH
authors.lastname: Wu
authors.affiliation: Department of Pediatrics, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China.
authors.forename: Xiao-Qing
authors.initials: XQ
authors.lastname: Chen
authors.affiliation: Department of Pediatrics, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China.
authors.forename: Jing
authors.initials: J
authors.lastname: Lü
authors.affiliation: Department of Pediatrics, The First Affiliated Hospital with Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, People's Republic of China.
authors.forename: Ming-Jie
authors.initials: MJ
authors.lastname: Wang
mesh_terms: D058186:Acute Kidney Injury / Q000188:drug therapy*; D000818:Animals; D001806:Blood Urea Nitrogen; D002460:Cell Line; D003404:Creatinine / Q000097:blood; D005966:Glucuronidase / Q000652:urine; D051547:Heme Oxygenase-1 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D006538:Heptanoic Acids / Q000494:pharmacology*; D007093:Imidazoles / Q000494:pharmacology; D007931:Leucyl Aminopeptidase / Q000652:urine; D008297:Male; D008315:Malondialdehyde / Q000378:metabolism; D010080:Oxazoles / Q000494:pharmacology; D047493:PPAR alpha / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D009195:Peroxidase / Q000378:metabolism; D010766:Phosphorylation; D011401:Promoter Regions, Genetic / Q000235:genetics; D011524:Protoporphyrins / Q000494:pharmacology; D011725:Pyridines / Q000494:pharmacology; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D044067:Receptors, Lipoxin / Q000819:agonists; D015427:Reperfusion Injury / Q000188:drug therapy*; D014443:Tyrosine / Q000031:analogs & derivatives / Q000494:pharmacology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism*
chemical_list: C530770:5(S),6(R)-7-trihydroxyheptanoic acid, methyl ester; C449302:GW 6471; D006538:Heptanoic Acids; D007093:Imidazoles; D010080:Oxazoles; D047493:PPAR alpha; D011524:Protoporphyrins; D011725:Pyridines; D012333:RNA, Messenger; D044067:Receptors, Lipoxin; C017803:zinc protoporphyrin; D014443:Tyrosine; D008315:Malondialdehyde; D003404:Creatinine; D009195:Peroxidase; D051547:Heme Oxygenase-1; D048051:p38 Mitogen-Activated Protein Kinases; C033263:N-acetyl-beta-glucuronidase; D005966:Glucuronidase; D007931:Leucyl Aminopeptidase; C093642:SB 203580
keywords: BML-111; heme oxygenase-1; ischemia/reperfusion injury; kidney; lipoxins; p38 mitogen-activated protein kinase; peroxisome proliferator-activated receptor-α