MicroRNA-34a is induced via p53 during cisplatin nephrotoxicity and contributes to cell survival.
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.
Bhatt
Kirti
K
Department of Cellular Biology and Anatomy,Medical College of Georgia and Charlie Norwood VA Medical Center, 1459 Laney Walker Blvd., Augusta, GA 30912, USA.
Zhou
Li
L
Mi
Qing-Sheng
QS
Huang
Shuang
S
She
Jin-Xiong
JX
Dong
Zheng
Z
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*
C551848:MIRN34a microRNA, mouse; D035683:MicroRNAs; D016159:Tumor Suppressor Protein p53; D002945:Cisplatin
Nat Cell Biol. 2009 Jul;11(7):881-9
19543271
Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3432-7
17360662
Semin Nephrol. 2003 Sep;23(5):460-4
13680535
J Am Soc Nephrol. 2008 Nov;19(11):2069-75
18832437
Mol Cell. 2007 Jun 8;26(5):731-43
17540598
J Biol Chem. 2008 Mar 7;283(10):6572-83
18162465
J Am Soc Nephrol. 2008 Nov;19(11):2159-69
18776119
Am J Physiol Renal Physiol. 2000 May;278(5):F726-36
10807584
Nat Cell Biol. 2009 Mar;11(3):228-34
19255566
J Am Soc Nephrol. 2005 Jul;16(7):1985-92
15901768
Annu Rev Genomics Hum Genet. 2007;8:215-39
17506656
Clin J Am Soc Nephrol. 2009 Jul;4(7):1255-66
19581401
Am J Physiol. 1996 Apr;270(4 Pt 2):F700-8
8967349
J Am Soc Nephrol. 2008 Nov;19(11):2150-8
18776121
Am J Physiol Renal Physiol. 2004 Mar;286(3):F572-80
14612380
Am J Physiol Renal Physiol. 2003 Oct;285(4):F610-8
12865254
J Am Soc Nephrol. 2002 Apr;13(4):858-865
11912244
Am J Physiol Renal Physiol. 2007 Oct;293(4):F1282-91
17670903
Oncogene. 2008 Oct 6;27(45):5959-74
18836476
Am J Physiol Renal Physiol. 2003 Mar;284(3):F488-97
12419774
J Biol Chem. 2002 Nov 8;277(45):43377-88
12218054
Oncogene. 2009 Jun 25;28(25):2419-24
19421141
Biochem Pharmacol. 2007 May 1;73(9):1499-510
17291459
Oncogene. 2006 Jul 6;25(29):4056-66
16491117
Kidney Int. 2004 Dec;66(6):2202-13
15569309
Mol Cell. 2007 Jun 8;26(5):745-52
17540599
J Biol Chem. 2007 Jan 26;282(4):2636-45
17130128
Cell Cycle. 2007 Jul 1;6(13):1586-93
17554199
Arch Toxicol. 2004 Mar;78(3):147-55
14551673
Life Sci. 2008 Oct 10;83(15-16):550-6
18761355
Proc Natl Acad Sci U S A. 2007 Sep 25;104(39):15472-7
17875987
Curr Opin Nephrol Hypertens. 2009 Jul;18(4):317-23
19424061
Cell. 2005 Jul 15;122(1):6-7
16009126
Kidney Int. 2007 Jul;72(1):53-62
17410096
J Pharmacol Exp Ther. 2002 Jul;302(1):8-17
12065694
Curr Biol. 2007 Aug 7;17(15):1298-307
17656095
Am J Physiol Renal Physiol. 2004 Feb;286(2):F378-84
12965891
Kidney Int. 2009 Aug;76(3):277-85
19436334
Kidney Int. 2008 May;73(9):994-1007
18272962
J Pharmacol Exp Ther. 2007 Jul;322(1):8-15
17400889
Am J Physiol Renal Physiol. 2005 Jul;289(1):F166-74
15701814
Kidney Int. 2008 Sep;74(5):631-40
18509315
Am J Physiol. 1996 Dec;271(6 Pt 2):F1211-6
8997395
Nature. 2007 Jun 28;447(7148):1130-4
17554337
Am J Physiol Renal Physiol. 2004 Dec;287(6):F1140-7
15315938
J Biol Chem. 2005 Sep 2;280(35):31230-9
15983031