title: MicroRNA-34a is induced via p53 during cisplatin nephrotoxicity and contributes to cell survival.
abstract: MicroRNAs are small noncoding RNAs that are produced endogenously and have emerged as important regulators in pathophysiological conditions such as development and tumorigenesis. Very little is known about the regulation of microRNAs in renal diseases, including acute kidney injury (AKI). In this study, we examined the regulation of microRNA-34a (miR-34a) in experimental models of cisplatin-induced AKI and nephrotoxicity. By Northern blot and real-time polymerase chain reaction analyses, we detected an induction of miR-34a in vitro during cisplatin treatment of mouse proximal tubular cells and also in vivo during cisplatin nephrotoxicity in C57BL/6 mice. In cultured cells, miR-34a was induced within a few hours. In mice, miR-34a induction was detectable in renal tissues after 1 d of cisplatin treatment and increased to approximately four-fold of control at d 3. During cisplatin treatment, p53 was activated. Inhibition of p53 with pifithrin-α abrogated the induction of miR-34a during cisplatin treatment of proximal tubular cells. In vivo, miR-34a induction by cisplatin was abrogated in p53-deficient mice, a result that further confirms a role for p53 in miR-34a induction during cisplatin nephrotoxicity. Functionally, antagonism of miR-34a with specific antisense oligonucleotides increased cell death during cisplatin treatment. Collectively, the results suggest that miR-34a is induced via p53 during cisplatin nephrotoxicity and may play a cytoprotective role for cell survival.
authors.affiliation: Department of Cellular Biology and Anatomy,Medical College of Georgia and Charlie Norwood VA Medical Center, 1459 Laney Walker Blvd., Augusta, GA 30912, USA.
authors.forename: Kirti
authors.initials: K
authors.lastname: Bhatt
authors.forename: Li
authors.initials: L
authors.lastname: Zhou
authors.forename: Qing-Sheng
authors.initials: QS
authors.lastname: Mi
authors.forename: Shuang
authors.initials: S
authors.lastname: Huang
authors.forename: Jin-Xiong
authors.initials: JX
authors.lastname: She
authors.forename: Zheng
authors.initials: Z
authors.lastname: Dong
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002945:Cisplatin / Q000633:toxicity*; D005786:Gene Expression Regulation / Q000187:drug effects; D007668:Kidney / Q000187:drug effects* / Q000473:pathology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism*
chemical_list: C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin
references.citation: Nat Cell Biol. 2009 Jul;11(7):881-9
references.pmid: 19543271
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3432-7
references.pmid: 17360662
references.citation: Semin Nephrol. 2003 Sep;23(5):460-4
references.pmid: 13680535
references.citation: J Am Soc Nephrol. 2008 Nov;19(11):2069-75
references.pmid: 18832437
references.citation: Mol Cell. 2007 Jun 8;26(5):731-43
references.pmid: 17540598
references.citation: J Biol Chem. 2008 Mar 7;283(10):6572-83
references.pmid: 18162465
references.citation: J Am Soc Nephrol. 2008 Nov;19(11):2159-69
references.pmid: 18776119
references.citation: Am J Physiol Renal Physiol. 2000 May;278(5):F726-36
references.pmid: 10807584
references.citation: Nat Cell Biol. 2009 Mar;11(3):228-34
references.pmid: 19255566
references.citation: J Am Soc Nephrol. 2005 Jul;16(7):1985-92
references.pmid: 15901768
references.citation: Annu Rev Genomics Hum Genet. 2007;8:215-39
references.pmid: 17506656
references.citation: Clin J Am Soc Nephrol. 2009 Jul;4(7):1255-66
references.pmid: 19581401
references.citation: Am J Physiol. 1996 Apr;270(4 Pt 2):F700-8
references.pmid: 8967349
references.citation: J Am Soc Nephrol. 2008 Nov;19(11):2150-8
references.pmid: 18776121
references.citation: Am J Physiol Renal Physiol. 2004 Mar;286(3):F572-80
references.pmid: 14612380
references.citation: Am J Physiol Renal Physiol. 2003 Oct;285(4):F610-8
references.pmid: 12865254
references.citation: J Am Soc Nephrol. 2002 Apr;13(4):858-865
references.pmid: 11912244
references.citation: Am J Physiol Renal Physiol. 2007 Oct;293(4):F1282-91
references.pmid: 17670903
references.citation: Oncogene. 2008 Oct 6;27(45):5959-74
references.pmid: 18836476
references.citation: Am J Physiol Renal Physiol. 2003 Mar;284(3):F488-97
references.pmid: 12419774
references.citation: J Biol Chem. 2002 Nov 8;277(45):43377-88
references.pmid: 12218054
references.citation: Oncogene. 2009 Jun 25;28(25):2419-24
references.pmid: 19421141
references.citation: Biochem Pharmacol. 2007 May 1;73(9):1499-510
references.pmid: 17291459
references.citation: Oncogene. 2006 Jul 6;25(29):4056-66
references.pmid: 16491117
references.citation: Kidney Int. 2004 Dec;66(6):2202-13
references.pmid: 15569309
references.citation: Mol Cell. 2007 Jun 8;26(5):745-52
references.pmid: 17540599
references.citation: J Biol Chem. 2007 Jan 26;282(4):2636-45
references.pmid: 17130128
references.citation: Cell Cycle. 2007 Jul 1;6(13):1586-93
references.pmid: 17554199
references.citation: Arch Toxicol. 2004 Mar;78(3):147-55
references.pmid: 14551673
references.citation: Life Sci. 2008 Oct 10;83(15-16):550-6
references.pmid: 18761355
references.citation: Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15472-7
references.pmid: 17875987
references.citation: Curr Opin Nephrol Hypertens. 2009 Jul;18(4):317-23
references.pmid: 19424061
references.citation: Cell. 2005 Jul 15;122(1):6-7
references.pmid: 16009126
references.citation: Kidney Int. 2007 Jul;72(1):53-62
references.pmid: 17410096
references.citation: J Pharmacol Exp Ther. 2002 Jul;302(1):8-17
references.pmid: 12065694
references.citation: Curr Biol. 2007 Aug 7;17(15):1298-307
references.pmid: 17656095
references.citation: Am J Physiol Renal Physiol. 2004 Feb;286(2):F378-84
references.pmid: 12965891
references.citation: Kidney Int. 2009 Aug;76(3):277-85
references.pmid: 19436334
references.citation: Kidney Int. 2008 May;73(9):994-1007
references.pmid: 18272962
references.citation: J Pharmacol Exp Ther. 2007 Jul;322(1):8-15
references.pmid: 17400889
references.citation: Am J Physiol Renal Physiol. 2005 Jul;289(1):F166-74
references.pmid: 15701814
references.citation: Kidney Int. 2008 Sep;74(5):631-40
references.pmid: 18509315
references.citation: Am J Physiol. 1996 Dec;271(6 Pt 2):F1211-6
references.pmid: 8997395
references.citation: Nature. 2007 Jun 28;447(7148):1130-4
references.pmid: 17554337
references.citation: Am J Physiol Renal Physiol. 2004 Dec;287(6):F1140-7
references.pmid: 15315938
references.citation: J Biol Chem. 2005 Sep 2;280(35):31230-9
references.pmid: 15983031