title: miR-21 promotes renal fibrosis in diabetic nephropathy by targeting PTEN and SMAD7.
abstract: The cytokine transforming growth factor (TGF)-β1 plays a central role in diabetic nephropathy (DN) with data implicating the miRNA (miR) miR-21 as a key modulator of its prosclerotic actions. In the present study, we demonstrate data indicating that miR-21 up-regulation positively correlates with the severity of fibrosis and rate of decline in renal function in human DN. Furthermore, concomitant analyses of various models of fibrotic renal disease and experimental DN, confirm tubular miR-21 up-regulation. The fibrotic changes associated with increased miR-21 levels are proposed to include the regulation of TGF-β1-mediated mothers against decapentaplegic homolog 3 (SMAD3)- and phosphoinositide 3-kinase (PI3K)-dependent signalling pathways via co-ordinated repression of mothers against decapentaplegic homolog 7 (SMAD7) and phosphatase and tensin homologue (PTEN) respectively. This represents a previously uncharacterized interaction axis between miR-21 and PTEN-SMAD7. Targeting of these proteins by miR-21 resulted in de-repression of the respective pathways as reflected by increases in SMAD3 and V-Akt murine thymoma viral oncogene homolog 1 (AKT) phosphorylation. Many of the changes typically induced by TGF-β1, including phosphorylation of signalling mediators, were further enhanced by miR-21. Collectively, these data present a unified model for a key role for miR-21 in the regulation of renal tubular extracellular matrix (ECM) synthesis and accumulation and provide important insights into the molecular pathways implicated in the progression of DN.
authors.affiliation: JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Domain, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia Department of Medicine, Central Clinical School, Monash University, 75 Commercial Road, Melbourne, VIC 3004, Australia.
authors.forename: Aaron D
authors.initials: AD
authors.lastname: McClelland
authors.affiliation: Department of Nephrology & Hypertension, Rabin Medical Center, Petah Tikva, 4941492, Israel; Felsenstein Medical Research Institute, Rabin Medical Center, Petah Tikva, 49100, Israel; Sackler School of Medicine, Tel Aviv University, Ramat Aviv 69978, Israel.
authors.forename: Michal
authors.initials: M
authors.lastname: Herman-Edelstein
authors.affiliation: Division of Nephrology & Hypertension, Oregon Health & Science University, Portland, OR 97239, U.S.A.
authors.forename: Radko
authors.initials: R
authors.lastname: Komers
authors.affiliation: Department of Medicine, Central Clinical School, Monash University, 75 Commercial Road, Melbourne, VIC 3004, Australia.
authors.forename: Jay C
authors.initials: JC
authors.lastname: Jha
authors.affiliation: Division of Cell Signalling and Metabolism, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia.
authors.forename: Catherine E
authors.initials: CE
authors.lastname: Winbanks
authors.affiliation: Department of Medicine, Central Clinical School, Monash University, 75 Commercial Road, Melbourne, VIC 3004, Australia.
authors.forename: Shinji
authors.initials: S
authors.lastname: Hagiwara
authors.affiliation: Division of Cell Signalling and Metabolism, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia.
authors.forename: Paul
authors.initials: P
authors.lastname: Gregorevic
authors.affiliation: JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Domain, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia Phillip.Kantharidis@bakerIDI.edu.au.
authors.forename: Phillip
authors.initials: P
authors.lastname: Kantharidis
authors.affiliation: JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Domain, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia.
authors.forename: Mark E
authors.initials: ME
authors.lastname: Cooper
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency / Q000235:genetics; D016022:Case-Control Studies; D002460:Cell Line; D003094:Collagen / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000139:chemically induced / Q000150:complications; D003928:Diabetic Nephropathies / Q000209:etiology / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D005355:Fibrosis; D005919:Glomerular Filtration Rate; D006801:Humans; D007687:Kidney Tubules, Proximal / Q000187:drug effects / Q000378:metabolism* / Q000473:pathology / Q000503:physiopathology; D018345:Mice, Knockout; D035683:MicroRNAs / Q000235:genetics / Q000378:metabolism*; D051059:PTEN Phosphohydrolase / Q000378:metabolism*; D010766:Phosphorylation; D011379:Prognosis; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D034622:RNA Interference; D017207:Rats, Sprague-Dawley; D012720:Severity of Illness Index; D015398:Signal Transduction; D051906:Smad7 Protein / Q000235:genetics / Q000378:metabolism*; D014162:Transfection; D053773:Transforming Growth Factor beta1 / Q000494:pharmacology; D015854:Up-Regulation
chemical_list: D001057:Apolipoproteins E; C524940:MIRN21 microRNA, human; C531950:MIRN21 microRNA, mouse; D035683:MicroRNAs; D051906:Smad7 Protein; C497808:Smad7 protein, rat; D053773:Transforming Growth Factor beta1; C546082:mirn21 microRNA, rat; D003094:Collagen; C494920:Akt1 protein, rat; D051057:Proto-Oncogene Proteins c-akt; D051059:PTEN Phosphohydrolase; C487216:Pten protein, rat
keywords: biopsy; diabetic nephropathy; fibrosis; micro ribonucleic acid (RNA); signalling; transforming growth factor (TGF)-β1