Adeerjiang Yilinuer, Gan Xiao-Xue, Li Wen-Ting, Li Qin-Tian, Jiang Yi-Qi, Zhu Xia, Hu Chen-Ming, Wang Pan-Xia, Jiang Sheng
Department of Endocrinology, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, People's Republic of China.
State Key Laboratory of Pathogenesis, Prevention and Treatment of High Incidence Diseases in Central Asia, Urumqi, People's Republic of China.
Int J Gen Med. 2025 May 28;18:2757-2768. doi: 10.2147/IJGM.S524138. eCollection 2025.
Diabetic kidney disease (DKD), a major microvascular complication of diabetes, affects 30-40% of patients and is the leading cause of end-stage renal disease. The Wnt/β-catenin signaling pathway plays a dual role in DKD pathogenesis: its moderate activation protects against hyperglycemia-induced mesangial apoptosis, while chronic overactivation exacerbates renal fibrosis, podocyte injury, and tubular dysfunction. This review synthesizes current evidence on the pathway's context-dependent mechanisms. Emerging therapeutic strategies-including small-molecule inhibitors (eg, Dickkopf-1), monoclonal antibodies, and natural compounds like curcumin and Salvia miltiorrhiza extracts-show preclinical promise in modulating Wnt/β-catenin activity. However, clinical translation faces challenges such as pathway redundancy, off-target effects, and the need for precise dosing to balance protective and injurious outcomes. Recent advances in biomarker discovery (eg, urinary β-catenin) and ongoing clinical trials highlight the pathway's potential as a therapeutic target. Future research must prioritize patient stratification, combination therapies (eg, Wnt inhibitors + RAAS blockers), and mechanistic studies to address unresolved controversies in Wnt signaling dynamics. This work underscores the therapeutic implications of targeting Wnt/β-catenin in DKD while advocating for a nuanced approach to harness its protective roles.
糖尿病肾病（DKD）是糖尿病的一种主要微血管并发症，影响30%-40%的患者，是终末期肾病的主要原因。Wnt/β-连环蛋白信号通路在DKD发病机制中起双重作用：其适度激活可防止高血糖诱导的系膜细胞凋亡，而长期过度激活则会加剧肾纤维化、足细胞损伤和肾小管功能障碍。本综述综合了关于该通路依赖于背景的机制的现有证据。新兴的治疗策略，包括小分子抑制剂（如Dickkopf-1）、单克隆抗体以及姜黄素和丹参提取物等天然化合物，在调节Wnt/β-连环蛋白活性方面显示出临床前的前景。然而，临床转化面临着诸如通路冗余、脱靶效应以及需要精确给药以平衡保护和损伤结果等挑战。生物标志物发现（如尿β-连环蛋白）的最新进展和正在进行的临床试验突出了该通路作为治疗靶点的潜力。未来的研究必须优先考虑患者分层、联合治疗（如Wnt抑制剂+肾素-血管紧张素-醛固酮系统阻滞剂）以及机制研究，以解决Wnt信号动力学中未解决的争议。这项工作强调了在DKD中靶向Wnt/β-连环蛋白的治疗意义，同时倡导采用细致入微的方法来发挥其保护作用。
