酪氨酸激酶抑制剂 tyrphostin AG126 可减轻大鼠肾缺血/再灌注损伤。

The tyrosine kinase inhibitor tyrphostin AG126 reduces renal ischemia/reperfusion injury in the rat.

作者信息

Chatterjee Prabal K, Patel Nimesh S A, Kvale Espen O, Brown Paul A J, Stewart Keith N, Britti Domenico, Cuzzocrea Salvatore, Mota-Filipe Helder, Thiemermann Christoph

机构信息

Department of Experimental Medicine, Nephrology & Critical Care, William Harvey Research Institute, Queen Mary - University of London, London, United Kingdom.

出版信息

Kidney Int. 2003 Nov;64(5):1605-19. doi: 10.1046/j.1523-1755.2003.00254.x.

DOI:10.1046/j.1523-1755.2003.00254.x

PMID:14531792

Abstract

BACKGROUND

We investigate the effects of tyrphostin AG126, an inhibitor of tyrosine kinase activity, on the renal dysfunction and injury caused by ischemia/reperfusion (I/R) of the kidney.

METHODS

Tyrphostin AG126 (5 mg/kg intraperitoneally) was administered to male Wistar rats 30 minutes prior to bilateral renal ischemia for 45 minutes followed by reperfusion for up to 48 hours. Biochemical markers of renal dysfunction and injury were measured and renal sections assessed for renal injury. Expression of inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2) and formation of nitrotyrosine and poly (ADP) ribose (PAR) were assessed using immunohistochemistry. Rat proximal tubular cells (PTCs) were incubated with interferon-gamma (100 IU/mL), bacterial lipopolysaccharide (10 microg/mL), and with increasing concentrations of tyrphostin AG126 (0.0001-1 mmol/L) for 24 hours. Nitric oxide production was measured in both plasma from rats subjected to I/R and in incubation medium from PTCs.

RESULTS

After 6 hours of reperfusion, tyrphostin AG126 significantly reduced the increase in serum and urinary indicators of renal dysfunction and injury caused by I/R and reduced histologic evidence of renal injury. Tyrphostin AG126 also improved renal function (after 24 and 48 hours of reperfusion) and reduced the histologic signs of renal injury (after 48 hours of reperfusion). Tyrphostin AG126 reduced the expression of iNOS and nitric oxide levels in both rat plasma and in PTC cultures, as well as expression of COX-2. Tyrphostin AG126 also reduced nitrotyrosine and PAR formation, suggesting reduction of nitrosative stress and poly (ADP-ribose) polymerase (PARP) activation, respectively.

CONCLUSION

Taken together, these results show that tyrphostin AG126 significantly reduces the renal dysfunction and injury caused by I/R of the kidney. We propose that inhibition of tyrosine kinase activity may be useful against renal I/R injury.

摘要

背景

我们研究酪氨酸激酶活性抑制剂 tyrphostin AG126 对肾脏缺血/再灌注（I/R）所致肾功能障碍和损伤的影响。

方法

在雄性 Wistar 大鼠双侧肾脏缺血 45 分钟前 30 分钟，腹腔注射 tyrphostin AG126（5 毫克/千克），随后进行长达 48 小时的再灌注。检测肾功能障碍和损伤的生化标志物，并评估肾脏切片的肾损伤情况。使用免疫组织化学评估诱导型一氧化氮合酶（iNOS）和环氧化酶-2（COX-2）的表达以及硝基酪氨酸和聚（ADP）核糖（PAR）的形成。将大鼠近端肾小管细胞（PTCs）与干扰素-γ（100 国际单位/毫升）、细菌脂多糖（10 微克/毫升）以及浓度递增的 tyrphostin AG126（0.0001 - 1 毫摩尔/升）孵育 24 小时。检测 I/R 大鼠血浆和 PTCs 孵育培养基中的一氧化氮生成量。

结果

再灌注 6 小时后，tyrphostin AG126 显著降低了 I/R 所致血清和尿液中肾功能障碍及损伤指标的升高，并减少了肾损伤的组织学证据。tyrphostin AG126 还改善了肾功能（再灌注 24 小时和 48 小时后），并减轻了肾损伤的组织学征象（再灌注 48 小时后）。tyrphostin AG126 降低了大鼠血浆和 PTCs 培养物中 iNOS 的表达及一氧化氮水平，以及 COX-2 的表达。tyrphostin AG126 还减少了硝基酪氨酸和 PAR 的形成，分别提示亚硝化应激和聚（ADP-核糖）聚合酶（PARP）激活的降低。