miR-21 promotes renal fibrosis in diabetic nephropathy by targeting PTEN and SMAD7.

The cytokine TGF-β1 plays a central role in diabetic nephropathy (DN) with data implicating the microRNA miR-21 as a key modulator of its prosclerotic actions. Here, we present data indicating that miR-21 upregulation positively correlates with the severity of fibrosis and rate of decline in renal function in human diabetic nephropathy. Furthermore, concomitant analyses of various models of fibrotic renal disease and experimental diabetic nephropathy, confirm tubular miR-21 upregulation. The fibrotic changes associated with increased miR-21 levels are proposed to include the regulation of TGF-β1-mediated SMAD3-dependent and PI3K-dependent signalling pathways via coordinated repression of SMAD7 and PTEN respectively. This represents a previously uncharacterised interaction axis between miR-21 and PTEN/SMAD7. Targeting of these proteins by miR-21 resulted in derepression of the respective pathways as reflected by increases in SMAD3 and 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 ECM synthesis and accumulation and provide important insights into the molecular pathways implicated in the progression of diabetic nephropathy.