Chiao H, Kohda Y, McLeroy P, Craig L, Linas S, Star R A
Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235-8856, USA.
Kidney Int. 1998 Sep;54(3):765-74. doi: 10.1046/j.1523-1755.1998.00075.x.
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.
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.
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).
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.
我们之前的研究表明，即使在缺血6小时后开始使用α-黑素细胞刺激素（α-MSH），它也能减轻缺血/再灌注损伤。α-MSH可抑制中性粒细胞聚集和一氧化氮生成。为了确定α-MSH在中性粒细胞途径中的相对重要性，我们在中性粒细胞作用最小或不存在的损伤模型中研究了α-MSH的作用。
我们研究了α-MSH在以下模型中的作用：（1）细胞间黏附分子-1（ICAM-1）基因敲除小鼠和野生型小鼠，均经历40分钟缺血和24小时再灌注；（2）分离的肾脏，先进行20分钟的体内缺血，然后在无中性粒细胞的情况下进行1小时的体外灌注。为了初步探究α-MSH对肾小管的直接作用，我们研究了α-MSH对内毒素/干扰素-γ处理的小鼠皮质肾小管细胞中一氧化氮（NO）的影响。
缺血后，ICAM-1基因敲除小鼠的中性粒细胞浸润比野生型小鼠少75%。尽管中性粒细胞相对较少，但α-MSH仍能抑制ICAM-1基因敲除小鼠的肾损伤。在离体灌注缺血肾脏模型中，α-MSH还能显著保护肾小球滤过率（GFR）和肾小管钠重吸收。α-MSH与一氧化氮抑制剂未表现出协同作用。最后，α-MSH使小鼠皮质肾小管细胞（MCT）中的亚硝酸盐生成减少20%，这与在培养的小鼠巨噬细胞系（RAW细胞）中的平行观察结果相似。
我们得出结论，当中性粒细胞作用最小或不存在时，α-MSH可减轻肾损伤，这表明α-MSH可抑制肾损伤的非中性粒细胞依赖途径。体外钠吸收的保留以及培养的MCT细胞中亚硝酸盐生成的抑制表明，α-MSH通过直接作用于肾小管来抑制肾小管损伤。
