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: Sheng-Hua Wu, Xiao-Qing Chen, Jing Lü, Ming-Jie Wang
• Journal: Inflammation (Inflammation) Vol. 39 Issue 2 Pg. 611-24 (Apr 2016) ISSN: 1573-2576 [Electronic] United States
• PMID: 26597893 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• 5(S),6(R)-7-trihydroxyheptanoic acid, methyl ester
• GW 6471
• Heptanoic Acids
• Imidazoles
• Oxazoles
• PPAR alpha
• Protoporphyrins
• Pyridines
• RNA, Messenger
• Receptors, Lipoxin
• zinc protoporphyrin
• Tyrosine
• Malondialdehyde
• Creatinine
• Peroxidase
• Heme Oxygenase-1
• p38 Mitogen-Activated Protein Kinases
• N-acetyl-beta-glucuronidase
• Glucuronidase
• Leucyl Aminopeptidase
• SB 203580

Topics

• Acute Kidney Injury (drug therapy)
• Animals
• Blood Urea Nitrogen
• Cell Line
• Creatinine (blood)
• Glucuronidase (urine)
• Heme Oxygenase-1 (antagonists & inhibitors, genetics, metabolism)
• Heptanoic Acids (pharmacology)
• Imidazoles (pharmacology)
• Leucyl Aminopeptidase (urine)
• Male
• Malondialdehyde (metabolism)
• Oxazoles (pharmacology)
• PPAR alpha (antagonists & inhibitors, genetics, metabolism)
• Peroxidase (metabolism)
• Phosphorylation
• Promoter Regions, Genetic (genetics)
• Protoporphyrins (pharmacology)
• Pyridines (pharmacology)
• RNA, Messenger (biosynthesis, genetics)
• Rats
• Rats, Sprague-Dawley
• Receptors, Lipoxin (agonists)
• Reperfusion Injury (drug therapy)
• Tyrosine (analogs & derivatives, pharmacology)
• p38 Mitogen-Activated Protein Kinases (antagonists & inhibitors, metabolism)