卡维地洛改善顺铂致肾小管上皮细胞凋亡

Carvedilol prevents the apoptosis of renal tubular cells in cisplatin-induced ARF

目的观察顺铂致急性肾衰竭(ARF)中肾小管上皮细胞凋亡情况及卡维地洛(carvedilol)对其影响,并探讨其作用机制。方法雄性Wistar大鼠随机分为盐水对照组、顺铂组、卡维地洛对照组、卡维地洛治疗组。测定BUN、Scr、尿乙酰氨基葡糖苷酶(NAG)、肾组织丙二醛(MDA)与超氧化物歧化酶(SOD)的含量。苏木素-伊红染色(HE)观察肾脏病理改变。原位缺口末端标记法(TUNEL)与DNA电泳观察肾小管上皮细胞的凋亡。Western印迹检测caspase-3的蛋白表达。结果顺铂组大鼠BUN、Scr、尿NAG升高;肾脏病理改变加重;大量的肾小管上皮细胞凋亡;MDA含量增加,SOD活性降低;caspase-3的蛋白表达增加。上述指标在卡维地洛治疗组均得到改善,BUN从(58．33±19．93)降至(28．74±19．62)mmol／L;Scr从(425．56±97．96)降至(253．90±134．87)μmol／L;NAG从(224．77±75．86)降至(137．52±26．38)U／L;MDA从(18．13±7．01)降至(9．74±1．68)nmol／mg蛋白;SOD从(30．05±12．20)升至(64．67±20．64)U／mg蛋白;caspase-3的蛋白表达从1．94±0．73降至1．25±0．52;细胞凋亡从(42．5±12．6)％降至(23．7±8．4)％;肾组织病理损害也明显改善。结论肾小管上皮细胞凋亡是顺铂致ARF的重要原因之一。卡维地洛能减轻顺铂的肾毒性,降低肾小管上皮细胞凋亡,其机制可能与减少活性氧(ROS)的产生,部分抑制了caspase依赖的凋亡途径有关。

Objective To study the apoptosis of renal tubular cells in acute renal failure induced by cisplatin and the effect of carvedilol on such apoptosis. Methods Male wistar rats were randomly divided into four groups： group 1 received 0.85% saline 1 ml/200 g ip. single dose; group 2 received cisplatin 10 mg/kg ip; group 3 received carvedilol 15 mg/kg qd ig; group 4 received carvedilol 15 mg/kg qd ig. for 6 days, and cisplatin 10 mg/kg ip at day 4. Nephrotoxicity was assessed by measuring BUN, Scr, urinary acetylglucosaminidase （NAG） and histopathology of kidney 3 days after the cisplatin treatment. Tubular cell apoptosis was examined by TUNEL and DNA agarose gel electrophoresis. Protein expression of caspase-3 as well as malondialdehyde （MDA） content and superoxided dismutase （SOD） activity were detected in kidneys. Results Cisplatin induced a significant elevation in Scr, BUN, urinary NAG, renal tubular cell apoptosis, expression of caspase-3 as well as MDA content and severe morphology changes, while decreased the renal SOD activity. However, carvedilol improved above status of nephrotoxicity. Conclusions Renal tubular cell apoptosis is one of the important causes of cisplatin-induced ARF. Pretreatment with carvedilol can protect the rats from cisplatin-induced nephrotoxicity by reducing ROS, decreasing the apoptosis of renal tubulan cells ,and partly inhibiting the caspase-dependent way.