Abstract
Dysregulation of specific microRNAs or Wnt/β-catenin signaling pathway is critically implicated in the pathogenesis of various renal diseases. However, the relationship between microRNAs and Wnt/β-catenin signaling in diabetes-induced glomerular sclerosis remains unknown. Here, we found that decreased miR-29a expression and attenuated Wnt/β-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 β-catenin and blocked the expressions of profibrotic gene markers, including DKK1 (a Wnt antagonist), TGF-β1 and fibronectin, in glomerular mesangium. Moreover, in the normal mice treated with miR-29a inhibitor, renal fibrosis was induced with an attenuated Wnt/β-catenin signaling activity. Consistently, the constructed miR-29a transgenic mice that supported sustained Wnt/β-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/β-catenin signaling in cultured mesangial cells and functions to protect cell apoptosis and fibrosis. Importantly, we showed that activation of Wnt/β-catenin signaling in cultured mesangial cells by transfecting the β-catenin (Δ45) mutant or by a GSK-3β inhibitor reversely upregulated miR29a. Our findings suggest that the reciprocal relationship between miR-29a and DKK1/Wnt/β-catenin signaling may play an important part in protecting renal fibrogenesis.
Highlights
Dysregulation of specific microRNAs or Wnt/β-catenin signaling pathway is critically implicated in the pathogenesis of various renal diseases
We investigated whether miR-29a signaling participates in mesangial fibrosis induced by hyperglycemia, and elucidated the relationship between miR-29a action and the DKK1/Wnt/β-catenin signaling in diabetes-induced renal injury
To determine the potential role of miR-29 signaling in glomerular fibrosis induced by diabetes, streptozotocin (STZ)-treated mice were used in the study
Summary
Dysregulation of specific microRNAs or Wnt/β-catenin signaling pathway is critically implicated in the pathogenesis of various renal diseases. Gain of miR-29a function in diabetic mice substantially increased the expression of β-catenin and blocked the expressions of profibrotic gene markers, including DKK1 (a Wnt antagonist), TGF-β1 and fibronectin, in glomerular mesangium. Upregulation of specific microRNAs, including miR-192, miR-200b/c, miR-217, miR-216a and miR-377, has been reported to promote glomerular fibrosis and hypertrophy in various animal models[16,17] Among these microRNAs, miR-192 regulated by TGF-β1 is known to target E-Box repressors Zeb[1] and Zeb[2], which leads to activation of Zeb1/2-regulated genes including collagen type 1 α2, miR-200b/c, miR217 and miR-216a18. The increased miR-200b/c continue to target Zeb[1] and Zeb[2] to auto-stimulate their expression[19] Both miR-217 and miR-216a are known to promote mesangial cell expansion and hypertrophy by silencing PTEN (phosphatase and tenin homolog), the major negative regulator of Akt signaling[20]. Whether other microRNAs play roles in diabetic glomerulosclerosis remains to be explored and characterized
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