Alpha-melanocyte-stimulating hormone protects against renal injury after ischemia in mice and rats

• Published in: The Journal of clinical investigation Vol. 99; no. 6; pp. 1165 - 1172
• Main Authors: Chiao, H, Kohda, Y, McLeroy, P, Craig, L, Housini, I, Star, R A
• Format: Journal Article
• Language: English
• Published: United States 15.03.1997
• Subjects: alpha-MSH - administration & dosage; alpha-MSH - pharmacology; Animals; Blotting, Northern; Cell Adhesion Molecules - genetics; Chemokines - genetics; Drug Administration Schedule; Female; Kidney - blood supply; Kidney - drug effects; Kidney - pathology; Male; Mice; Mice, Inbred BALB C; Nitrates - metabolism; Nitric Oxide Synthase - biosynthesis; Rats; Rats, Sprague-Dawley; Reperfusion Injury - drug therapy; Reperfusion Injury - metabolism; Reperfusion Injury - pathology; RNA, Messenger - analysis
• ISSN: 0021-9738
• DOI: 10.1172/jci119272

Reperfusion after ischemia induces cytokines, chemoattractant chemokines, adhesion molecules, and nitric oxide (NO). The resultant neutrophil adherence and NO potentiates renal injury. alpha-Melanocyte-stimulating hormone (alpha-MSH) is a potent anti-inflammatory agent that inhibits neutrophil migration and production of neutrophil chemokines and NO. Since neutrophils and NO promote renal ischemic injury, we sought to determine if alpha-MSH inhibits renal injury in a model of bilateral renal ischemia. alpha-MSH significantly reduced ischemia-induced renal damage, measured by changes in renal histology and plasma blood urea nitrogen and creatinine in mice. alpha-MSH significantly decreased tubule necrosis, neutrophil plugging, and capillary congestion. Delay of alpha-MSH treatment for 6 h after ischemia also significantly inhibited renal damage. alpha-MSH also significantly inhibited ischemic damage in rats. To begin to determine the mechanism of action of alpha-MSH, we measured its effects on mediators of neutrophil trafficking and induction of the inducible isoform of NO synthase-II. alpha-MSH inhibited ischemia-induced increases in mRNA for the murine neutrophil chemokine KC/IL-8. alpha-MSH also inhibited induction of mRNA for the adhesion molecule ICAM-1, which is known to be critical in renal ischemic injury. alpha-MSH inhibited nitration of kidney proteins and induction of NO synthase-II. We conclude: (a) alpha-MSH protects against renal ischemia/reperfusion injury; and (b) it may act, in part, by inhibiting the maladaptive activation of genes that cause neutrophil activation and adhesion, and induction of NO synthase.