Prevention of neutrophil extravasation by hepatocyte growth factor leads to attenuations of tubular apoptosis and renal dysfunction in mouse ischemic kidneys.
Ischemia and reperfusion (I/R) injuries occur in numerous organs under pathophysiological conditions. In this process, neutrophils play important roles in eliciting parenchymal injuries. Using a murine model of renal I/R, we show that hepatocyte growth factor (HGF) is a natural ligand that inhibits endothelial injuries and neutrophil extravasation. In mice after renal I/R, plasma HGF levels increased, along with c-Met/HGF receptor phosphorylation in the vascular endothelium. However, this c-Met activation was transient, associated with a decrease in endogenous HGF level, and followed by neutrophil infiltration and renal dysfunction. Suppression of endothelial c-Met phosphorylation by anti-HGF IgG led to rapid progressions of neutrophil extravasation, tubular apoptosis, and renal dysfunction. Inversely, enhancement of the c-Met activation by exogenous HGF blocked endothelial/tubular apoptotic injuries and acute renal failure. In this process, HGF prevented endothelial nuclear factor kappaB activation and inhibited induction of an adhesion molecule (ICAM-1), resulting in attenuated vascular edema and neutrophil infiltration. Thus, we conclude that 1) the HGF/c-Met system of endothelial cells confers an initial barrier to block neutrophil infiltration, and 2) transient and insufficient HGF production allows manifestation of postischemic renal failure. Our study provides a rationale for why HGF supplementation elicits therapeutic effects in ischemic kidneys.
Mizuno
Shinya
S
Division of Molecular Regenerative Medicine, Department of Regenerative Medicine, Course of Advanced Medicine, Osaka University Graduate School of Medicine, 2-2-B7 Yamadaoka, Suita 565-0871, Japan.
Nakamura
Toshikazu
T
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D002465:Cell Movement / Q000502:physiology*; D004195:Disease Models, Animal; D042783:Endothelial Cells / Q000378:metabolism; D005260:Female; D017228:Hepatocyte Growth Factor / Q000378:metabolism*; D007150:Immunohistochemistry; D007668:Kidney / Q000098:blood supply; D007674:Kidney Diseases / Q000378:metabolism / Q000473:pathology*; D007684:Kidney Tubules / Q000378:metabolism / Q000473:pathology; D051379:Mice; D008813:Mice, Inbred ICR; D009504:Neutrophils / Q000166:cytology*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D015427:Reperfusion Injury / Q000378:metabolism / Q000473:pathology*
D017228:Hepatocyte Growth Factor; D019859:Proto-Oncogene Proteins c-met