Paricalcitol prevents cisplatin-induced renal injury by suppressing apoptosis and proliferation

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• 作者：Jeong Woo Park^a ; Jung Won Cho^b ; Soo Yeon Joo^b ; Chang Seong Kim^a ; Joon Seok Choi^a ; Eun Hui Bae^a ; Seong Kwon Ma^a ; Suhn Hee Kim^c ; JongUn Lee^b ; Soo Wan Kim^a ; ^{skimw@chonnam.ac.kr}
• 关键词：Cisplatin ; Acute kidney injury ; Paricalcitol ; Cyclin-dependent kinase inhibitor p27 ; Transforming growth factor-尾1 ; Tumor suppressor protein p53
• 刊名：European Journal of Pharmacology
• 出版年：2012
• 期刊代码：24_00142999
• 类别：neu
• 出版时间：15 May, 2012
• 卷：683
• 期：1-3
• 页码：301-309
• 文件大小：1923 K

摘要

The present study was performed to examine whether paricalcitol may prevent the cisplatin-induced kidney injury. Furthermore, potential molecular mechanisms underlying the protective effect of paricalcitol were explored. Male Sprague-Dawley rats were treated with vehicle (n = 12), cisplatin (n = 12, 6 mg/kg/day, i.p.), or cisplatin + paricalcitol (n = 12, 0.2 渭g/kg/day, s.c.) for 4 days. In another series of experiment, HK-2 cells were treated with cisplatin (50 渭M), with or without paricalcitol (0.2 ng/ml). Paricalcitol counteracted the cisplatin-induced decline in renal function. Paricalcitol also suppressed the expression of TGF-尾1, Smad signaling, and the subsequent epithelial-to-mesenchymal process in cisplatin-treated rats. The expression of P-p53 and p21 was increased in cisplatin-induced nephropathy. These changes were completely prevented or significantly attenuated with paricalcitol co-treatment. The expression of p27^kip1 was increased in cisplatin-treated rats, which was, however, further augmented by the paricalcitol co-treatment. In HK-2 cells, cisplatin increased the expression of p-ERK1/2 and P-p38. Cisplatin also increased the expression of fibronectin and CTGF. Cisplatin increased the expression of pro-apoptotic markers. The expression of CDK2 and Cyclin E as well as that of PCNA was increased. These changes were completely prevented or significantly attenuated by the paricalcitol pretreatment. In contrast, cisplatin increased the expression of p27^kip1, which was further augmented by the paricalcitol-pretreatment. These results suggest that paricalcitol may ameliorate cisplatin-induced renal injury by suppressing the fibrotic, apoptotic and proliferative factors. Its underlying mechanisms may include inhibition of TGF-尾1, mitogen-activated protein kinase signaling, p53-induced apoptosis, and augmentation of p27^kip1.