title: Suppression of microRNA-29 expression by TGF-β1 promotes collagen expression and renal fibrosis.
abstract: Synthesis and deposition of extracellular matrix (ECM) within the glomerulus and interstitium characterizes renal fibrosis, but the mechanisms underlying this process are incompletely understood. The profibrotic cytokine TGF-β1 modulates the expression of certain microRNAs (miRNAs), suggesting that miRNAs may have a role in the pathogenesis of renal fibrosis. Here, we exposed proximal tubular cells, primary mesangial cells, and podocytes to TGF-β1 to examine its effect on miRNAs and subsequent collagen synthesis. TGF-β1 reduced expression of the miR-29a/b/c/family, which targets collagen gene expression, and increased expression of ECM proteins. In both resting and TGF-β1-treated cells, ectopic expression of miR-29 repressed the expression of collagens I and IV at both the mRNA and protein levels by targeting the 3'untranslated region of these genes. Furthermore, we observed low levels of miR-29 in three models of renal fibrosis representing early and advanced stages of disease. Administration of the Rho-associated kinase inhibitor fasudil prevented renal fibrosis and restored expression of miR-29. Taken together, these data suggest that TGF-β1 inhibits expression of the miR-29 family, thereby promoting expression of ECM components. Pharmacologic modulation of these miRNAs may have therapeutic potential for progressive renal fibrosis.
authors.affiliation: JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Division, Baker IDI Heart and Diabetes Institute, Melbourne, Australia.
authors.forename: Bo
authors.initials: B
authors.lastname: Wang
authors.forename: Radko
authors.initials: R
authors.lastname: Komers
authors.forename: Rosemarie
authors.initials: R
authors.lastname: Carew
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Winbanks
authors.forename: Bei
authors.initials: B
authors.lastname: Xu
authors.forename: Michal
authors.initials: M
authors.lastname: Herman-Edelstein
authors.forename: Philip
authors.initials: P
authors.lastname: Koh
authors.forename: Merlin
authors.initials: M
authors.lastname: Thomas
authors.forename: Karin
authors.initials: K
authors.lastname: Jandeleit-Dahm
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
authors.forename: Phillip
authors.initials: P
authors.lastname: Kantharidis
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D000818:Animals; D015820:Cadherins / Q000235:genetics; D002478:Cells, Cultured; D003094:Collagen / Q000235:genetics*; D003928:Diabetic Nephropathies / Q000378:metabolism; D005355:Fibrosis; D005786:Gene Expression Regulation; D007668:Kidney / Q000378:metabolism / Q000473:pathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D035683:MicroRNAs / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology
chemical_list: D020413:3' Untranslated Regions; D015820:Cadherins; C526366:MIRN29 microRNA, rat; D035683:MicroRNAs; D012333:RNA, Messenger; D053773:Transforming Growth Factor beta1; D003094:Collagen
references.citation: Endocrinology. 2000 Mar;141(3):1196-208
references.pmid: 10698197
references.citation: J Am Soc Nephrol. 2007 Jan;18(1):165-75
references.pmid: 17135399
references.citation: J Am Soc Nephrol. 2005 Feb;16(2):363-73
references.pmid: 15625075
references.citation: FEBS Lett. 2009 Jun 18;583(12):2009-14
references.pmid: 19450585
references.citation: J Am Soc Nephrol. 2010 Mar;21(3):438-47
references.pmid: 20056746
references.citation: J Biol Chem. 2011 Apr 1;286(13):11837-48
references.pmid: 21310958
references.citation: Kidney Int. 1992 Apr;41(4):891-7
references.pmid: 1387433
references.citation: Kidney Int. 2003 May;63(5):1776-84
references.pmid: 12675853
references.citation: Nat Cell Biol. 2009 Jul;11(7):881-9
references.pmid: 19543271
references.citation: Lab Invest. 2010 Jan;90(1):98-103
references.pmid: 19901913
references.citation: Hepatology. 2011 Jan;53(1):209-18
references.pmid: 20890893
references.citation: Methods. 2010 Dec;52(4):375-81
references.pmid: 20621190
references.citation: Diabetes. 2010 Jul;59(7):1794-802
references.pmid: 20393144
references.citation: J Am Soc Nephrol. 2010 Aug;21(8):1317-25
references.pmid: 20488955
references.citation: Proc Natl Acad Sci U S A. 2008 Apr 15;105(15):5874-8
references.pmid: 18390668
references.citation: Arthritis Rheum. 2010 Jun;62(6):1733-43
references.pmid: 20201077
references.citation: Proc Natl Acad Sci U S A. 2007 Feb 27;104(9):3432-7
references.pmid: 17360662
references.citation: J Am Soc Nephrol. 2006 Sep;17(9):2484-94
references.pmid: 16914537
references.citation: Diabetes. 2011 Jan;60(1):280-7
references.pmid: 20952520
references.citation: Pharm Res. 2008 Oct;25(10):2447-61
references.pmid: 18633694
references.citation: Am J Physiol. 1998 Dec;275(6):F962-71
references.pmid: 9843914
references.citation: Cancer Res. 2007 Sep 1;67(17):7972-6
references.pmid: 17804704
references.citation: J Am Soc Nephrol. 2002 Mar;13(3):630-638
references.pmid: 11856766
references.citation: Kidney Int. 2003 Dec;64(6):2009-19
references.pmid: 14633123
references.citation: Cancer Res. 2006 Dec 15;66(24):11745-53
references.pmid: 17178870
references.citation: Cancer Res. 2006 May 1;66(9):4662-71
references.pmid: 16651417
references.citation: N Engl J Med. 2001 Sep 20;345(12):861-9
references.pmid: 11565518
references.citation: Genes Dev. 2006 Mar 1;20(5):515-24
references.pmid: 16510870
references.citation: EMBO Rep. 2008 Jun;9(6):582-9
references.pmid: 18483486
references.citation: Cell Cycle. 2008 Oct;7(20):3112-8
references.pmid: 18927505
references.citation: Am J Respir Cell Mol Biol. 2008 Jan;38(1):95-104
references.pmid: 17673689
references.citation: Am J Pathol. 2009 Oct;175(4):1380-8
references.pmid: 19729486
references.citation: Eur J Pharmacol. 2002 Nov 29;455(2-3):169-74
references.pmid: 12445583
references.citation: J Hypertens. 2004 Sep;22(9):1787-96
references.pmid: 15311108
references.citation: J Hypertens. 2007 May;25(5):1053-63
references.pmid: 17414670
references.citation: Diabetes. 2008 Jun;57(6):1683-92
references.pmid: 18356410
references.citation: Nephrology (Carlton). 2008 Apr;13(2):139-46
references.pmid: 18275502
references.citation: Nat Cell Biol. 2008 May;10(5):593-601
references.pmid: 18376396
references.citation: PLoS Biol. 2009 Nov;7(11):e1000238
references.pmid: 19901979
references.citation: J Clin Invest. 2001 Dec;108(12):1853-63
references.pmid: 11748269
references.citation: Kidney Int. 2003 Aug;64(2):565-71
references.pmid: 12846751
references.citation: J Clin Invest. 2002 Aug;110(3):341-50
references.pmid: 12163453
references.citation: Eur J Pharmacol. 2003 Mar 7;464(1):63-7
references.pmid: 12600696
references.citation: Hypertension. 2010 Apr;55(4):974-82
references.pmid: 20194304
references.citation: J Biol Chem. 2008 May 30;283(22):14910-4
references.pmid: 18411277
references.citation: Proc Natl Acad Sci U S A. 2008 Sep 2;105(35):13027-32
references.pmid: 18723672
references.citation: J Biol Chem. 2010 Jul 23;285(30):23457-65
references.pmid: 20501654
references.citation: FASEB J. 2008 Dec;22(12):4126-35
references.pmid: 18716028
references.citation: Diabetes. 2006 Jun;55(6):1651-9
references.pmid: 16731827
references.citation: Kidney Int. 2003 Sep;64(3):844-56
references.pmid: 12911534
references.citation: Kidney Int. 2011 Feb;79(4):432-42
references.pmid: 20962741
references.citation: J Clin Invest. 2009 Jun;119(6):1417-9
references.pmid: 19487817
references.citation: Lab Invest. 2007 Jun;87(6):548-58
references.pmid: 17401436
references.citation: RNA. 2009 Jan;15(1):21-32
references.pmid: 19029310
references.citation: Diabetes. 2008 Sep;57(9):2461-9
references.pmid: 18511846