A small molecule C5a receptor antagonist protects kidneys from ischemia/reperfusion injury in rats
A small molecule C5a receptor antagonist protects kidneys from ischemia/reperfusion injury in rats
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DOI：
10.1046/j.1523-1755.2003.00737.x
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发表时间：
2003-01-01
影响因子：
19.6
通讯作者：
Taylor, SM
中科院分区：
文献类型：
--
作者：
Arumugam, TV;Shiels, IA;Taylor, SM
背景。C5a与许多病理生理状况有关，包括肾缺血/再灌注（I/R）损伤。我们检测了一种新的特异性C5a受体拮抗剂，环化合物AcF-[OPdChaWR]是否能减轻I/ r诱导的大鼠肾损伤。雌性Wistar大鼠进行肾缺血（60 min）和再灌注（5 h）。大鼠缺血前分别给予5%乙醇/生理盐水中1 mg/kg IV或25%乙醇/生理盐水中10 mg/kg PO。I/R损伤的特征是显著的组织出血，微血管通透性增加，肾组织肿瘤坏死因子- α (tnf - α)和髓过氧化物酶（MPO）水平升高，血清肌酐和天冬氨酸转氨酶（AST）水平升高，血尿增多。用C5a受体（C5aR）拮抗剂（1mg /kg IV或10mg /kg PO）进行缺血前治疗可显著抑制或预防I/ r诱导的血尿、血管渗漏、组织中tnf - α和MPO的水平以及血清中AST和肌酐的水平。对经拮抗剂预处理的I/R动物肾脏的组织学检查显示，与未用药的I/R大鼠相比，组织损伤明显减少。然而，这种拮抗剂不抑制补体介导的红细胞裂解，表明膜攻击复合物（MAC）的形成未受损害。研究结果首次表明，无论是静脉注射还是口服，人类和大鼠C5a受体的选择性拮抗剂都能显著保护大鼠肾脏免受I/R损伤。我们得出结论，C5a是肾I/R损伤的重要致病因子，C5a受体拮抗剂可能是人类预期肾再灌注损伤的有效治疗药物。
Background. C5a has been implicated in numerous pathophysiological conditions, including ischemia/reperfusion (I/R) injury of the kidney. We examined whether a novel and specific C5a receptor antagonist, the cyclic compound AcF-[OPdChaWR] could moderate I/R-induced renal injury in rats.Methods. Female Wistar rats were subjected to renal ischemia (60 min) and reperfusion (5 h). Rats were treated with either 1 mg/kg IV in 5% ethanol/saline or 10 mg/kg PO in 25% ethanol/saline prior to ischemia. I/R injury was characterized by significant tissue hemorrhage with increased microvascular permeability, elevated renal tissue levels of tumor necrosis factor-alpha (TNF-alpha) and myeloperoxidase (MPO), increased serum levels of creatinine and aspartate aminotransferase (AST) and hematuria.Results. Pre-ischemic treatment with the C5a receptor (C5aR) antagonist (1 mg/kg IV or 10 mg/kg PO) substantially inhibited or prevented I/R-induced hematuria, vascular leakage, tissue levels of TNF-alpha and MPO, and serum levels of AST and creatinine. Histological examination of kidneys from antagonist pretreated I/R animals showed a marked reduction in tissue damage compared to drug-free I/R rats. This antagonist, however, did not inhibit complement-mediated lysis of red blood cells, suggesting unimpaired formation of the membrane attack complex (MAC).Conclusions. The results demonstrate for the first time that a selective antagonist of both human and rat C5a receptors, given either intravenously or orally, significantly protects the kidney from I/R injury in the rat. We conclude that C5a is an important pathogenic agent in renal I/R injury, and that C5a receptor antagonists may be useful therapeutic agents for the pretreatment of anticipated renal reperfusion injury in humans.