Yao Yu-Xuan, Tang Chen, Si Feng-Lei, Lv Ji-Cheng, Shi Su-Fang, Zhou Xu-Jie, Liu Li-Jun, Zhang Hong
Renal Division, Peking University First Hospital, Peking University Institute of Nephrology, Beijing, China.
Ministry of Education, Key Laboratory of Renal Disease, Ministry of Health of China, Key Laboratory of Chronic Kidney Disease Prevention and Treatment (Peking University), Beijing, China.
Ren Fail. 2025 Dec;47(1):2478488. doi: 10.1080/0886022X.2025.2478488. Epub 2025 Apr 15.
It has been proved that glucagon-like peptide-1 receptor (GLP1R) agonists have positive effects on renal outcomes in diabetic patients. However, it remains unknown whether GLP1R agonists could provide similar protection against other kidney diseases.
We performed two-sample Mendelian randomization (MR) analyses to determine the causal effects of GLP1R agonists on multiple kidney diseases. Exposure to GLP1R agonist was proxied by the available cis-eQTLs for GLP1R. Primary outcomes included the risk assessment for diabetic nephropathy, IgA nephropathy, membranous nephropathy, nephrotic syndrome, chronic kidney disease, acute glomerulonephritis, chronic glomerulonephritis and calculus of kidney/ureter. Type 2 diabetes and body mass index were used as positive control. Two-stage network MR analyses were conducted to assess the mediation effect of inflammatory proteins on the relationships between GLP1R agonists and kidney diseases.
After meta-analyses of both discovery and validation cohorts, genetically proxied GLP1R agonist was found to significantly associated with a decreased risk of diabetic nephropathy (OR = 0.72, 95%CI = 0.54-0.97, = 0.031) and IgA nephropathy (OR = 0.58, 95%CI = 0.36-0.94, = 0.027). Two-stage network MR revealed that there was an indirect effect of GLP1R agonist on IgA nephropathy through signaling lymphocytic activation molecule family member 1 (SLAMF1), with a mediated proportion of 34.27% (95% CI, 1.47-67.03%, = 0.041) of the total effect.
The findings of current study presented genetic proof for the potential protective effects of GLP1R agonists in the development of diabetic nephropathy and IgA nephropathy, offering a novel sight for future mechanistic and clinical applications.
已证实胰高血糖素样肽-1受体（GLP1R）激动剂对糖尿病患者的肾脏结局有积极影响。然而，GLP1R激动剂是否能对其他肾脏疾病提供类似的保护作用仍不清楚。
我们进行了两样本孟德尔随机化（MR）分析，以确定GLP1R激动剂对多种肾脏疾病的因果效应。通过GLP1R的可用顺式-eQTL来代表GLP1R激动剂的暴露情况。主要结局包括糖尿病肾病、IgA肾病、膜性肾病、肾病综合征、慢性肾脏病、急性肾小球肾炎、慢性肾小球肾炎以及肾/输尿管结石的风险评估。2型糖尿病和体重指数用作阳性对照。进行两阶段网络MR分析，以评估炎症蛋白对GLP1R激动剂与肾脏疾病之间关系的中介作用。
在对发现队列和验证队列进行荟萃分析后，发现基因代表的GLP1R激动剂与糖尿病肾病风险降低显著相关（OR = 0.72，95%CI = 0.54 - 0.97，P = 0.031）以及IgA肾病（OR = 0.58，95%CI = 0.36 - 0.94，P = 0.027）。两阶段网络MR显示，GLP1R激动剂通过信号淋巴细胞激活分子家族成员1（SLAMF1）对IgA肾病有间接效应，介导比例占总效应的34.27%（95%CI，1.47 - 67.03%，P = 0.041）。
本研究结果为GLP1R激动剂在糖尿病肾病和IgA肾病发生发展中的潜在保护作用提供了遗传学证据，为未来的机制研究和临床应用提供了新的视角。
