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.
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Research Article|
November 11 2015
miR-21 promotes renal fibrosis in diabetic nephropathy by targeting PTEN and SMAD7
Aaron D. McClelland;
Aaron D. McClelland
1
*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
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Michal Herman-Edelstein;
Michal Herman-Edelstein
1
‡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
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Radko Komers;
Radko Komers
§Division of Nephrology & Hypertension, Oregon Health & Science University, Portland, OR 97239, U.S.A.
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Jay C. Jha;
Jay C. Jha
†Department of Medicine, Central Clinical School, Monash University, 75 Commercial Road, Melbourne, VIC 3004, Australia
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Catherine E. Winbanks;
Catherine E. Winbanks
║Division of Cell Signalling and Metabolism, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia
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Shinji Hagiwara;
Shinji Hagiwara
†Department of Medicine, Central Clinical School, Monash University, 75 Commercial Road, Melbourne, VIC 3004, Australia
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Paul Gregorevic;
Paul Gregorevic
║Division of Cell Signalling and Metabolism, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia
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Phillip Kantharidis;
Phillip Kantharidis
2
*JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Domain, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia
Correspondence: Phillip Kantharidis (email [email protected]).
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Mark E. Cooper
Mark E. Cooper
2
*JDRF Danielle Alberti Memorial Centre for Diabetes Complications, Diabetes Domain, Baker IDI Heart and Diabetes Institute, 75 Commercial Road, Melbourne, VIC 3004, Australia
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Publisher: Portland Press Ltd
Received:
June 15 2015
Revision Received:
September 17 2015
Accepted:
September 25 2015
Accepted Manuscript online:
September 25 2015
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2015 Authors; published by Portland Press Limited
2015
Clin Sci (Lond) (2015) 129 (12): 1237–1249.
Article history
Received:
June 15 2015
Revision Received:
September 17 2015
Accepted:
September 25 2015
Accepted Manuscript online:
September 25 2015
Citation
Aaron D. McClelland, Michal Herman-Edelstein, Radko Komers, Jay C. Jha, Catherine E. Winbanks, Shinji Hagiwara, Paul Gregorevic, Phillip Kantharidis, Mark E. Cooper; miR-21 promotes renal fibrosis in diabetic nephropathy by targeting PTEN and SMAD7. Clin Sci (Lond) 1 December 2015; 129 (12): 1237–1249. doi: https://doi.org/10.1042/CS20150427
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