ALPHA-MELANOCYTE-STIMULATING HORMONE PROTECTS AGAINST RENAL INJURY AFTER ISCHEMIA IN MICE AND RATS

Reperfusion after ischemia induces cytokines, chemoattractant chemokin es, adhesion molecules, and nitric oxide (NO). The resultant neutrophi l adherence and NO potentiates renal injury. alpha-Melanocyte-stimulat ing hormone (alpha-MSH) is a potent anti-inflammatory agent that inhib its neutrophil migration and production of neutrophil chemokines and N O. Since neutrophils and NO promote renal ischemic injury, we sought t o determine if alpha-MSH inhibits renal injury in a model of bilateral renal ischemia. alpha-MSH significantly reduced ischemia-induced rena l damage, measured by changes in renal histology and plasma blood urea nitrogen and creatinine in mice. alpha-MSH significantly decreased tu bule necrosis, neutrophil plugging, and capillary congestion. Delay of alpha-MSK treatment for 6 h after ischemia also significantly inhibit ed renal damage. alpha-MSH also significantly inhibited ischemic damag e in rats. To begin to determine the mechanism of action of alpha-MSH, we measured its effects on mediators of neutrophil trafficking and in duction of the inducible isoform of NO synthase-II. alpha-MSH inhibite d ischemia-induced increases in mRNA for the murine neutrophil chemoki ne KC/IL-8. alpha-MSH also inhibited induction of mRNA for the adhesio n molecule ICAM-1, which is known to be critical in renal ischemic inj ury. alpha-MSH inhibited nitration of kidney proteins and induction of NO synthase-II. We conclude: (a) alpha-MSH protects against renal isc hemia/reperfusion injury; and (b) it may act, in part, by inhibiting t he maladaptive activation of genes that cause neutrophil activation an d adhesion, and induction of NO synthase.