DNMT3B aggravated renal fibrosis in diabetic kidney disease via activating Wnt/β-catenin signaling pathway

The incidence of diabetic kidney disease (DKD) has increased rapidly worldwide in recent decades, and DKD is the leading cause of chronic kidney disease. The Wnt/β-catenin pathway is widely recognized as a critical contributor to DKD. However, how this pathway is activated in DKD is still unknown. Recent studies have revealed that epigenetic mechanisms play key roles in DKD. DNA methylation is an epigenetic mechanism that is essential for regulating gene transcription. Here, we demonstrated that reducing the expression of DNMT3B, a DNA Methyltransferase, markedly decreased extracellular matrix (ECM) deposition and diabetic renal fibrosis (DRF). Furthermore, we found that DNMT3B activated the Wnt/β-catenin pathway by suppressing SFRP5 expression in HG-induced renal tubular epithelial cells. Mechanistically, we observed that DNMT3B increased the promoter methylation levels of sfrp5, which contributed to a decrease in SFRP5 protein expression. Additionally, Pharmacological disruption of DNA methylation (via 5-Aza) and genetic knockdown of DNMT3B suppressed the Wnt/β-catenin pathway, leading to the attenuation of ECM deposition and DRF. Thus, our study provides a novel understanding of the epigenetic regulation of DKD pathogenesis and a new therapeutic strategy for DKD by disrupting the Wnt/β-catenin pathway.

DNA methylation; DNA methyltransferase 3B (DNMT3B); Diabetic kidney disease (DKD); Secreted frizzled-relatd protein 5 (SFRP5); Wnt/β-catenin signalling pathway.