title: Paricalcitol prevents cisplatin-induced renal injury by suppressing apoptosis and proliferation.
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).
authors.affiliation: Department of Internal Medicine, Chonnam National University Medical School, Gwangju 501-757, Republic of Korea.
authors.forename: Jeong Woo
authors.initials: JW
authors.lastname: Park
authors.forename: Jung Won
authors.initials: JW
authors.lastname: Cho
authors.forename: Soo Yeon
authors.initials: SY
authors.lastname: Joo
authors.forename: Chang Seong
authors.initials: CS
authors.lastname: Kim
authors.forename: Joon Seok
authors.initials: JS
authors.lastname: Choi
authors.forename: Eun Hui
authors.initials: EH
authors.lastname: Bae
authors.forename: Seong Kwon
authors.initials: SK
authors.lastname: Ma
authors.forename: Suhn Hee
authors.initials: SH
authors.lastname: Kim
authors.forename: JongUn
authors.initials: J
authors.lastname: Lee
authors.forename: Soo Wan
authors.initials: SW
authors.lastname: Kim
mesh_terms: D058186:Acute Kidney Injury / Q000139:chemically induced / Q000378:metabolism / Q000503:physiopathology / Q000517:prevention & control*; D000818:Animals; D000970:Antineoplastic Agents / Q000009:adverse effects*; D017209:Apoptosis / Q000187:drug effects*; D001284:Atrophy; D050071:Bone Density Conservation Agents / Q000494:pharmacology / Q000627:therapeutic use; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects*; D002945:Cisplatin / Q000009:adverse effects*; D050760:Cyclin-Dependent Kinase Inhibitor p27 / Q000378:metabolism; D004872:Ergocalciferols / Q000494:pharmacology / Q000627:therapeutic use*; D006801:Humans; D007668:Kidney / Q000187:drug effects / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology; D020935:MAP Kinase Signaling System / Q000187:drug effects; D008297:Male; D020011:Protective Agents / Q000494:pharmacology / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism
chemical_list: D000970:Antineoplastic Agents; D050071:Bone Density Conservation Agents; D004872:Ergocalciferols; D020011:Protective Agents; D053773:Transforming Growth Factor beta1; D016159:Tumor Suppressor Protein p53; D050760:Cyclin-Dependent Kinase Inhibitor p27; C084656:paricalcitol; D002945:Cisplatin