Department of Pharmacology, Cardiovascular Research Laboratory, All India Institute of Medical Sciences, New Delhi-110029, India.
Department of Pathology, All India Institute of Medical Sciences, New Delhi-110029, India.
Eur J Pharmacol. 2015 Feb 5;748:54-60. doi: 10.1016/j.ejphar.2014.12.008. Epub 2014 Dec 13.
Nephrotoxicity is a major adverse effect of the widely used anticancer drug cisplatin. Oxidative stress, inflammation and apoptosis are implicated in the pathophysiology of cisplatin-induced acute renal injury. Moreover, cisplatin activates many signal transduction pathways involved in cell injury and death, particularly mitogen activated protein kinase (MAPK) pathway. With this background, we aimed to investigate the protective effect of telmisartan, a widely used antihypertensive drug, in cisplatin-induced nephrotoxicity model in rats. To accomplish this, male albino wistar rats (150-200 g) were divided into 6 groups: Normal, cisplatin-control, telmisartan (2.5, 5 and 10 mg/kg) and telmisartan per se treatment groups. Normal saline or telmisartan was administered orally to rats for 10 days and cisplatin was given on 7th day (8 mg/kg; i.p.) to induce nephrotoxicity. On 10th day, rats were killed and both the kidneys were harvested for biochemical, histopathological and molecular studies. Cisplatin injected rats showed depressed renal function, altered proxidant-antioxidant balance and acute tubular necrosis which was significantly normalized by telmisartan co-treatment. Furthermore, cisplatin administration activated MAPK pathway that caused tubular inflammation and apoptosis in rats. Telmisartan treatment significantly prevented MAPK mediated inflammation and apoptosis. Among the three doses studied telmisartan at 10 mg/kg dose showed maximum nephroprotective effect which could be due to maintenance of cellular redox status and inhibition of MAPK activation.
肾毒性是广泛使用的抗癌药物顺铂的主要不良反应。氧化应激、炎症和细胞凋亡都与顺铂诱导的急性肾损伤的病理生理学有关。此外，顺铂激活了许多涉及细胞损伤和死亡的信号转导途径，特别是丝裂原激活蛋白激酶（MAPK）途径。有鉴于此，我们旨在研究广泛使用的降压药物替米沙坦在顺铂诱导的大鼠肾毒性模型中的保护作用。为此，将雄性白化 Wistar 大鼠（150-200g）分为 6 组：正常组、顺铂对照组、替米沙坦（2.5、5 和 10mg/kg）和替米沙坦本身治疗组。正常生理盐水或替米沙坦口服给予大鼠 10 天，顺铂于第 7 天（8mg/kg；ip）给药以诱导肾毒性。第 10 天，处死大鼠，采集双侧肾脏进行生化、组织病理学和分子研究。注射顺铂的大鼠表现出肾功能下降、氧化还原平衡改变和急性肾小管坏死，替米沙坦联合治疗可显著改善这些变化。此外，顺铂给药激活了 MAPK 途径，导致大鼠肾小管炎症和细胞凋亡。替米沙坦治疗可显著预防 MAPK 介导的炎症和细胞凋亡。在研究的三种剂量中，替米沙坦 10mg/kg 剂量的肾保护作用最强，这可能是由于维持了细胞氧化还原状态并抑制了 MAPK 激活。
