Protective effects of miR-29a on diabetic glomerular dysfunction by modulation of DKK1/Wnt/β-catenin signaling

Dysregulation of specific microRNAs or Wnt/beta-catenin signaling pathway is critically implicated in the pathogenesis of various renal diseases. However, the relationship between microRNAs and Wnt/beta-catenin signaling in diabetes-induced glomerular sclerosis remains unknown. Here, we found that decreased miR-29a expression and attenuated Wnt/beta-catenin signaling were concomitantly detected in glomeruli of streptozotocin-induced diabetic mice. Gain of miR-29a function in diabetic mice substantially increased the expression of beta-catenin and blocked the expressions of profibrotic gene markers, including DKK1 (a Wnt antagonist), TGF-beta 1 and fibronectin, in glomerular mesangium. Moreover, in the normal mice treated with miR-29a inhibitor, renal fibrosis was induced with an attenuated Wnt/beta-catenin signaling activity. Consistently, the constructed miR-29a transgenic mice that supported sustained Wnt/beta-catenin signaling had the ability to block the expressions of profibrotic genes after induction of diabetes. We also demonstrated that miR-29a acts as a positive regulator of Wnt/beta-catenin signaling in cultured mesangial cells and functions to protect cell apoptosis and fibrosis. Importantly, we showed that activation of Wnt/beta-catenin signaling in cultured mesangial cells by transfecting the beta-catenin (Delta 45) mutant or by a GSK-3 beta inhibitor reversely upregulated miR29a. Our findings suggest that the reciprocal relationship between miR-29a and DKK1/Wnt/beta-catenin signaling may play an important part in protecting renal fibrogenesis.