title: MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β.
abstract: Nephrotoxicity is a major adverse effect of cisplatin-mediated chemotherapy in cancer patients. The pathogenesis of cisplatin-induced nephrotoxicity remains largely unclear, making it difficult to design effective renoprotective approaches. Here, we have examined the role of microRNAs (miRNAs) in cisplatin-induced nephrotoxicity. We show that cisplatin nephrotoxicity was not affected by overall depletion of both beneficial and detrimental miRNAs from kidney proximal tubular cells in mice in which the miRNA-generating enzyme Dicer had been conditionally knocked out. To identify miRNAs involved in cisplatin nephrotoxicity, we used microarray analysis to profile miRNA expression and identified 47 up-regulated microRNAs and 20 down-regulated microRNAs in kidney cortical tissues. One up-regulated miRNA was miR-375, whose expression was also induced in cisplatin-treated renal tubular cells. Interestingly, inhibition of miR-375 decreased cisplatin-induced apoptosis, suggesting that miR-375 is a cell-damaging or pro-apoptotic agent. Blockade of P53 or NF-κB attenuated cisplatin-induced miR-375 expression, supporting a role of P53 and NF-κB in miR-375 induction. We also identified hepatocyte nuclear factor 1 homeobox B (HNF-1β) as a key downstream target of miR-375. Of note, we further demonstrated that HNF-1β protected renal cells against cisplatin-induced apoptosis. Together, these results suggest that upon cisplatin exposure, P53 and NF-κB collaboratively induce miR-375 expression, which, in turn, represses HNF-1β activity, resulting in renal tubular cell apoptosis and nephrotoxicity.
authors.affiliation: From the Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.|the Department of Cellular Biology and Anatomy and.
authors.forename: Jielu
authors.initials: J
authors.lastname: Hao
authors.affiliation: the Department of Cellular Biology and Anatomy and.|the Antibody Drug Engineering Laboratory of Henan Province, Henan University School of Medicine, Kaifeng, Henan 475004, China.
authors.forename: Qiang
authors.initials: Q
authors.lastname: Lou
authors.affiliation: the Department of Cellular Biology and Anatomy and.
authors.forename: Qingqing
authors.initials: Q
authors.lastname: Wei
authors.affiliation: From the Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.|the Department of Cellular Biology and Anatomy and.
authors.forename: Shuqin
authors.initials: S
authors.lastname: Mei
authors.affiliation: From the Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.|the Department of Cellular Biology and Anatomy and.
authors.forename: Lin
authors.initials: L
authors.lastname: Li
authors.affiliation: Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia 30912.
authors.forename: Guangyu
authors.initials: G
authors.lastname: Wu
authors.affiliation: the Departments of Dermatology and Internal Medicine, Henry Ford Health System, Detroit, Michigan 48202, and.
authors.forename: Qing-Sheng
authors.initials: QS
authors.lastname: Mi
authors.affiliation: From the Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China, chlmei1954@126.com.
authors.forename: Changlin
authors.initials: C
authors.lastname: Mei
authors.affiliation: the Department of Cellular Biology and Anatomy and zdong@augusta.edu.|the Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000633:toxicity*; D017209:Apoptosis / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects*; D051539:Hepatocyte Nuclear Factor 1-beta / Q000235:genetics*; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics*; D043244:Ribonuclease III / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D035683:MicroRNAs; C540349:Mirn375 microRNA, mouse; D051539:Hepatocyte Nuclear Factor 1-beta; D043244:Ribonuclease III; D002945:Cisplatin
keywords: NF-κB; P53; apoptosis; cisplatin; gene regulation; kidney; microRNA (miRNA); nephrotoxicity