ALPHA-MELANOCYTE-STIMULATING HORMONE INHIBITS RENAL INJURY IN THE ABSENCE OF NEUTROPHILS

Background. We previously showed that alpha-melanocyte stimulating hor mone (alpha-MSH) decreases ischemia/reperfusion injury even when start ed six hours after ischemia. alpha-MSH inhibits both neutrophil accumu lation and nitric oxide production. To determine the relative importan ce of alpha-MSH on the neutrophil path way, we examined the effects of alpha-MSH in injury models where neutrophil effects are minimal or ab sent. Methods. We studied the effects of alpha-MSH in (1) intercellula r adhesion molecule-1 (ICAM-1) knock-out and background mice that were subjected to 40 minutes of ischemia and 24 hours reperfusion, and (2) isolated kidneys that were subjected to in vivo ischemia for 20 minut es and then perfused ex vivo for one hour without neutrophils. To begi n to search for direct tubule effects of alpha-MSH, we studied the eff ect of alpha-MSH on nitric oxide (NO) in endotoxin/interferon-gamma-tr eated mouse cortical tubule cells. Results. ICAM-1 knock-out mice had 75% less neutrophil infiltration than background mice after ischemia. Despite the relative lack of neutrophils, alpha-MSH inhibited renal in jury in ICAM-1 knock-out mice. alpha-MSH also significantly preserved GFR and tubular sodium reabsorption in the isolated perfused ischemic kidney model. alpha-MSH and a nitric oxide inhibitor did not exhibit s ynergy. Finally, alpha-MSH inhibited nitrite production by 20% in the mouse cortical tubule cells (MCT), similar to parallel observations in a cultured mouse macrophage line (RAW cells). Conclusions. We conclud e that alpha-MSH decreases renal injury when neutrophil effects are mi nimal or absent, indicating that alpha-MSH inhibits neutrophil-indepen dent pathways of renal injury. The preservation of sodium absorption e x vivo and inhibition of nitrite production in cultured MCT cells sugg ests that alpha-MSH inhibits tubular injury by direct tubular effects.