Ricardo S D, Levinson M E, DeJoseph M R, Diamond J R
Department of Medicine, Milton S. Hershey Medical Center, Hershey, Pennsylvania, USA.
Kidney Int. 1996 Dec;50(6):2002-10. doi: 10.1038/ki.1996.522.
Unilateral ureteral obstruction (UUO) is associated with an early and steadily increasing infiltration of macrophages into the renal cortical interstitium. As adhesion molecules may play an important role in macrophage recruitment following the mechanical disturbance after UUO, we delineated the time course of intercellular adhesion molecule (ICAM)-1 and vascular adhesion molecule (VCAM)-1 mRNA and protein expression. A significant 6.6- (P < 0.001), 2.6- (P < 0.025), 2.6- (P < 0.01), and 2.0-fold (P < 0.005) increase in ICAM-1 mRNA expression was observed at 12, 24, 48, and 96 hours after obstruction, respectively, in comparison to the contralateral unobstructed kidney (CUK). Despite an apparent relief of obstruction, four weeks following reversal of obstruction mRNA levels of ICAM-1 remained equivalent to the 96-hour obstructed kidney group. No significant difference in VCAM-1 mRNA expression was observed between the obstructed kidneys and CUK specimens. Immunohistochemistry revealed focal labeling of ICAM-1 on the apical and basolateral surface of the renal tubules, peritubular interstitium, and vessels of the renal cortex by 12 hours after UUO. In contrast, only faint staining for ICAM-1 protein was observed in the cortex from CUK specimens. The obstructed and CUK specimens exhibited diffuse immunolocalization of VCAM-1 in the cortical tubules and Bowman's capsular epithelium. In situ hybridization showed mRNA transcription for ICAM-1 localized in the peritubular interstitium and cortical tubules from obstructed kidneys. To lend mechanistic insight into the response of ICAM-1 to the mechanical disturbance after UUO, the expression of ICAM-1 mRNA was examined when freshly isolated proximal tubules were exposed to angiotensin II (1 to 100 microM) immediately after preparation. Levels of ICAM-1 mRNA were elevated 1.4-, 7.1-, and 3.7-fold when exposed to 10 microM, 100 microM, and 1000 microM of angiotensin II for one hour, respectively, when compared to control cultures. The addition of losartan to proximal tubules for one hour prior to angiotensin II stimulation decreased ICAM-1 levels to control values. In summary, this investigation demonstrates that ICAM-1 is important in the initiation of macrophage recruitment into the renal cortex of the obstructed kidney. These findings provide evidence that angiotensin II, produced after ureteral ligation as a result of tubular injury and dysfunction, may play a central role in the release of ICAM-1 from the proximal tubule epithelial cells.
单侧输尿管梗阻（UUO）与巨噬细胞早期且持续增加地浸润至肾皮质间质有关。由于黏附分子可能在UUO后机械性干扰引发的巨噬细胞募集过程中发挥重要作用，我们描绘了细胞间黏附分子（ICAM）-1和血管黏附分子（VCAM）-1 mRNA及蛋白表达的时间进程。与对侧未梗阻肾脏（CUK）相比，梗阻后12、24、48和96小时，ICAM-1 mRNA表达分别显著增加6.6倍（P < 0.001）、2.6倍（P < 0.025）、2.6倍（P < 0.01）和2.0倍（P < 0.005）。尽管梗阻明显缓解，但梗阻解除四周后，ICAM-1的mRNA水平仍与梗阻96小时的肾脏组相当。梗阻肾脏与CUK标本之间未观察到VCAM-1 mRNA表达的显著差异。免疫组织化学显示，UUO后12小时，ICAM-1在肾小管的顶端和基底外侧表面、肾小管周围间质及肾皮质血管处呈局灶性标记。相比之下，CUK标本的皮质中仅观察到ICAM-1蛋白的微弱染色。梗阻和CUK标本在皮质肾小管和鲍曼囊上皮中均表现出VCAM-1的弥漫性免疫定位。原位杂交显示，ICAM-1的mRNA转录定位于梗阻肾脏的肾小管周围间质和皮质肾小管。为深入了解ICAM-1对UUO后机械性干扰的反应机制，在新鲜分离的近端肾小管制备后立即将其暴露于血管紧张素II（1至100微摩尔），检测ICAM-1 mRNA的表达。与对照培养物相比，分别暴露于10微摩尔、100微摩尔和1000微摩尔血管紧张素II 1小时后，ICAM-1 mRNA水平分别升高1.4倍、7.1倍和3.7倍。在血管紧张素II刺激前1小时向近端肾小管中加入氯沙坦可使ICAM-1水平降至对照值。总之，本研究表明ICAM-1在启动巨噬细胞募集至梗阻肾脏的肾皮质过程中起重要作用。这些发现提供了证据，表明输尿管结扎后因肾小管损伤和功能障碍产生的血管紧张素II可能在近端肾小管上皮细胞释放ICAM-1中起核心作用。
