Alpha-melanocyte-stimulating hormone inhibits renal injury in the absence of neutrophils.
BACKGROUND
We previously showed that alpha-melanocyte stimulating hormone (alpha-MSH) decreases ischemia/reperfusion injury even when started six hours after ischemia. Alpha-MSH inhibits both neutrophil accumulation and nitric oxide production. To determine the relative importance of alpha-MSH on the neutrophil pathway, we examined the effects of alpha-MSH in injury models where neutrophil effects are minimal or absent.


METHODS
We studied the effects of alpha-MSH in (1) intercellular 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 minutes and then perfused ex vivo for one hour without neutrophils. To begin to search for direct tubule effects of alpha-MSH, we studied the effect of alpha-MSH on nitric oxide (NO) in endotoxin/interferon-gamma-treated 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 injury 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 synergy. 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 conclude that alpha-MSH decreases renal injury when neutrophil effects are minimal or absent, indicating that alpha-MSH inhibits neutrophil-independent pathways of renal injury. The preservation of sodium absorption ex vivo and inhibition of nitrite production in cultured MCT cells suggests that alpha-MSH inhibits tubular injury by direct tubular effects.
Chiao
H
H
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8856, USA.
Kohda
Y
Y
McLeroy
P
P
Craig
L
L
Linas
S
S
Star
R A
RA
D000818:Animals; D002478:Cells, Cultured; D005260:Female; D018799:Intercellular Adhesion Molecule-1 / Q000235:genetics / Q000502:physiology*; D007668:Kidney / Q000187:drug effects* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009504:Neutrophils / Q000502:physiology*; D009569:Nitric Oxide / Q000096:biosynthesis; D012333:RNA, Messenger / Q000032:analysis; D000521:alpha-MSH / Q000494:pharmacology*
D012333:RNA, Messenger; D018799:Intercellular Adhesion Molecule-1; D009569:Nitric Oxide; D000521:alpha-MSH