miR-21 promotes renal fibrosis in diabetic nephropathy by targeting PTEN and SMAD7
Aaron D McClelland1, Michal Herman-Edelstein2, Radko Komers3
1JDRF 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.
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.
Insights
MicroRNA-21 (miR-21) up-regulation is linked to diabetic nephropathy (DN) progression and kidney function decline. Targeting miR-21 may offer a novel therapeutic strategy for DN by modulating fibrotic pathways.
Area of Science:
- Nephrology
- Molecular Biology
- Genetics
Background:
- Diabetic nephropathy (DN) is a major complication of diabetes, characterized by progressive kidney fibrosis.
- Transforming growth factor-beta 1 (TGF-β1) is a key mediator of fibrosis in DN.
- MicroRNAs (miRNAs) are small non-coding RNAs that regulate gene expression and are implicated in various diseases, including DN.
Purpose of the Study:
- To investigate the role of miR-21 in the pathogenesis of DN.
- To elucidate the molecular mechanisms by which miR-21 contributes to renal fibrosis.
- To explore the potential of targeting miR-21 for DN treatment.
Main Methods:
- Correlation analysis of miR-21 levels with DN severity and renal function decline in human patients.
- Analysis of miR-21 expression in experimental models of fibrotic kidney disease and DN.
- Investigation of miR-21's effects on TGF-β1-mediated signaling pathways, including SMAD3, PI3K, SMAD7, and PTEN.
- Assessment of SMAD3 and AKT phosphorylation in response to miR-21 modulation.
Main Results:
- miR-21 up-regulation positively correlates with DN severity and renal function decline.
- miR-21 is up-regulated in tubular cells in DN and other fibrotic kidney diseases.
- miR-21 targets SMAD7 and PTEN, leading to de-repression of TGF-β1-mediated SMAD3 and PI3K/AKT signaling pathways.
- miR-21 enhances TGF-β1-induced changes, including extracellular matrix accumulation.
Conclusions:
- miR-21 plays a critical role in regulating renal tubular extracellular matrix synthesis and accumulation in DN.
- The interaction axis between miR-21, PTEN, and SMAD7 is a novel mechanism contributing to DN progression.
- Targeting miR-21 may represent a promising therapeutic strategy for managing DN.
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