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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.

Author information

1
From the Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China.
2
the Department of Cellular Biology and Anatomy and.
3
the Antibody Drug Engineering Laboratory of Henan Province, Henan University School of Medicine, Kaifeng, Henan 475004, China.
4
Department of Pharmacology and Toxicology, Medical College of Georgia at Augusta University and Charlie Norwood Veterans Affairs Medical Center, Augusta, Georgia 30912.
5
the Departments of Dermatology and Internal Medicine, Henry Ford Health System, Detroit, Michigan 48202, and.
6
From the Department of Nephrology, Changzheng Hospital, Second Military Medical University, Shanghai 200003, China, chlmei1954@126.com.
7
the Department of Cellular Biology and Anatomy and zdong@augusta.edu.
8
the Department of Nephrology, The Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, China.

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.

KEYWORDS:

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

PMID:
28119452
PMCID:
PMC5377773
DOI:
10.1074/jbc.M116.754929
[Indexed for MEDLINE]
Free PMC Article

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