title: Alpha-melanocyte-stimulating hormone protects against renal injury after ischemia in mice and rats.
abstract: 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.
authors.affiliation: Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8856, USA.
authors.forename: H
authors.initials: H
authors.lastname: Chiao
authors.forename: Y
authors.initials: Y
authors.lastname: Kohda
authors.forename: P
authors.initials: P
authors.lastname: McLeroy
authors.forename: L
authors.initials: L
authors.lastname: Craig
authors.forename: I
authors.initials: I
authors.lastname: Housini
authors.forename: R A
authors.initials: RA
authors.lastname: Star
mesh_terms: D000818:Animals; D015152:Blotting, Northern; D015815:Cell Adhesion Molecules / Q000235:genetics; D018925:Chemokines / Q000235:genetics; D004334:Drug Administration Schedule; D005260:Female; D007668:Kidney / Q000098:blood supply* / Q000187:drug effects / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D009566:Nitrates / Q000378:metabolism; D019001:Nitric Oxide Synthase / Q000096:biosynthesis; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology*; D000521:alpha-MSH / Q000008:administration & dosage / Q000494:pharmacology*
chemical_list: D015815:Cell Adhesion Molecules; D018925:Chemokines; D009566:Nitrates; D012333:RNA, Messenger; D000521:alpha-MSH; D019001:Nitric Oxide Synthase