1. Paricalcitol prevents cisplatin-induced renal injury by suppressing apoptosis and proliferation.
- Author
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Park JW, Cho JW, Joo SY, Kim CS, Choi JS, Bae EH, Ma SK, Kim SH, Lee J, and Kim SW
- Subjects
- Acute Kidney Injury chemically induced, Acute Kidney Injury metabolism, Acute Kidney Injury physiopathology, Animals, Atrophy, Bone Density Conservation Agents pharmacology, Bone Density Conservation Agents therapeutic use, Cell Line, Cyclin-Dependent Kinase Inhibitor p27 metabolism, Ergocalciferols pharmacology, Humans, Kidney drug effects, Kidney metabolism, Kidney pathology, Kidney physiopathology, MAP Kinase Signaling System drug effects, Male, Protective Agents pharmacology, Rats, Rats, Sprague-Dawley, Transforming Growth Factor beta1 metabolism, Tumor Suppressor Protein p53 metabolism, Acute Kidney Injury prevention & control, Antineoplastic Agents adverse effects, Apoptosis drug effects, Cell Proliferation drug effects, Cisplatin adverse effects, Ergocalciferols therapeutic use, Protective Agents therapeutic use
- Abstract
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 μg/kg/day, s.c.) for 4 days. In another series of experiment, HK-2 cells were treated with cisplatin (50 μM), with or without paricalcitol (0.2 ng/ml). Paricalcitol counteracted the cisplatin-induced decline in renal function. Paricalcitol also suppressed the expression of TGF-β1, 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-β1, mitogen-activated protein kinase signaling, p53-induced apoptosis, and augmentation of p27(kip1)., (Copyright © 2012 Elsevier B.V. All rights reserved.)
- Published
- 2012
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