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J Biol Chem. 2017 Mar 17;292(11):4571-4582. doi: 10.1074/jbc.M116.754929. Epub 2017 Jan 24.

MicroRNA-375 Is Induced in Cisplatin Nephrotoxicity to Repress Hepatocyte Nuclear Factor 1-β.

Hao J1,2, Lou Q2,3, Wei Q2, Mei S1,2, Li L1,2, Wu G4, Mi QS5, Mei C6, Dong Z7,8.

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From the Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
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.
Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia 30912.
the Departments of Dermatology and Internal Medicine, Henry Ford Health System, Detroit, Michigan 48202, and.
From the Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China,
the Department of Cellular Biology and Anatomy and
the Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.


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.


NF-κB; P53; apoptosis; cisplatin; gene regulation; kidney; microRNA (miRNA); nephrotoxicity

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