Department of Cardiology, First Affiliated Hospital of Fujian Medical University, 20 Chazhong Rd, Fuzhou 350005, China.
First Clinical College, Fujian Medical University, 20 Chazhong Rd, Fuzhou 350005, China; Department of Intensive Care Unit, Yichang Central Hospital, 183 Yiling Rd, Yichang 443003, China.
Eur J Pharmacol. 2014 Jan 15;723:15-22. doi: 10.1016/j.ejphar.2013.10.025. Epub 2013 Oct 24.
Contrast medium-induced acute kidney injury (CI-AKI) remains a leading cause of iatrogenic, drug-induced acute renal failure. This study aimed to investigate the protective effects of atorvastatin against renal tubular cell apoptosis in diabetic rats and the related mechanisms. CI-AKI was induced by intravenous administration of iopromide (12ml/kg) in streptozotocin-induced diabetic rats. Atorvastatin (ATO) was administered intragastrically at the dose of 5, 10 and 30mg/kg/d in different groups, respectively, for 5 days before iopromide injection. Renal function parameters, kidney histology, renal tubular cell apoptosis, the expression of apoptosis regulatory proteins, caspase-3 and Rho-associated protein kinase 1 (ROCK-1), and the phosphorylation of myosin phosphatase target subunit -1 (MYPT-1), were determined. Atorvastatin was shown to notably ameliorate contrast medium induced medullary damage, restore renal function, and suppress renal tubular apoptosis. Meanwhile, atorvastatin up-regulated the expression of Bcl-2, down-regulated the expression of Bax, caspase-3 and ROCK-1, restored the ratio of Bcl-2/Bax, and suppressed the phosphorylation of MYPT-1 in a dose-dependent manner. Thus, atorvastatin pretreatment could dose-dependently ameliorate the development of CI-AKI, which was partly attributed to its suppression of renal tubular cell apoptosis by inhibiting the Rho/ROCK pathway.
造影剂诱导的急性肾损伤（CI-AKI）仍然是医源性、药物性急性肾衰竭的主要原因。本研究旨在探讨阿托伐他汀对糖尿病大鼠肾小管细胞凋亡的保护作用及其相关机制。采用链脲佐菌素诱导的糖尿病大鼠静脉注射碘普罗胺（12ml/kg）诱导 CI-AKI。分别在不同组中给予阿托伐他汀（ATO）5、10 和 30mg/kg/d 灌胃 5 天，然后再注射碘普罗胺。测定肾功能参数、肾脏组织学、肾小管细胞凋亡、凋亡调节蛋白的表达、半胱天冬酶-3 和 Rho 相关蛋白激酶 1（ROCK-1）以及肌球蛋白磷酸酶靶亚单位-1（MYPT-1）的磷酸化。结果表明，阿托伐他汀可显著改善造影剂引起的皮质损伤，恢复肾功能，抑制肾小管凋亡。同时，阿托伐他汀呈剂量依赖性地上调 Bcl-2 的表达，下调 Bax、caspase-3 和 ROCK-1 的表达，恢复 Bcl-2/Bax 的比值，并抑制 MYPT-1 的磷酸化。因此，阿托伐他汀预处理可呈剂量依赖性地改善 CI-AKI 的发生，这部分归因于其通过抑制 Rho/ROCK 通路抑制肾小管细胞凋亡。
