Qu Lingling, Wang Tong, Kong Jing, Wu Xin, Li Qingxuan, Long Tianhua, An Xiaomin, Lu Yuwei, Mu Yao, Ran Yao, Guo Bing, Shi Mingjun
Department of Pathophysiology, Guizhou Medical University, Guiyang, 550025, Guizhou, China.
Department of Nephrology, Guiyang First People's Hospital, Guiyang, 550002, Guizhou, China.
Sci Rep. 2025 Jul 1;15(1):21070. doi: 10.1038/s41598-025-06713-3.
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.
近几十年来，糖尿病肾病（DKD）的发病率在全球范围内迅速上升，且DKD是慢性肾病的主要病因。Wnt/β-连环蛋白信号通路被广泛认为是DKD的关键促成因素。然而，该信号通路在DKD中是如何被激活的仍不清楚。最近的研究表明，表观遗传机制在DKD中起关键作用。DNA甲基化是一种对调节基因转录至关重要的表观遗传机制。在此，我们证明，降低DNA甲基转移酶DNMT3B的表达可显著减少细胞外基质（ECM）沉积和糖尿病肾纤维化（DRF）。此外，我们发现DNMT3B通过抑制高糖（HG）诱导的肾小管上皮细胞中SFRP5的表达来激活Wnt/β-连环蛋白信号通路。从机制上讲，我们观察到DNMT3B增加了sfrp5启动子的甲基化水平，这导致SFRP5蛋白表达减少。此外，DNA甲基化的药理学破坏（通过5-氮杂胞苷）和DNMT3B的基因敲低抑制了Wnt/β-连环蛋白信号通路，导致ECM沉积和DRF减轻。因此，我们的研究为DKD发病机制的表观遗传调控提供了新的认识，并通过破坏Wnt/β-连环蛋白信号通路为DKD提供了一种新的治疗策略。
