Tian Yan, Tian Ruixue, Juan He, Guo Yafan, Yan Pan, Cheng Yao, Li Rongshan, Wang Baodong
Department of Nephrology, Shanxi Provincial People's Hospital, The Fifth Clinical Medical College of Shanxi Medical University, 29 Shuang Ta East Street, Taiyuan 030012, China.
Department of Nephrology, Shanxi Provincial People's Hospital, The Fifth Clinical Medical College of Shanxi Medical University, 29 Shuang Ta East Street, Taiyuan 030012, China; Graduate School of Medicine, Nanchang University, 465 Bayi Road, Nanchang 330006, China.
Int Immunopharmacol. 2025 Jan 27;146:113877. doi: 10.1016/j.intimp.2024.113877. Epub 2024 Dec 18.
Effective therapeutic approaches for the treatment of diabetic nephropathy (DN) with irreversible deterioration of renal function are currently lacking. In this study, we aimed to investigate the ability of the glucagon-likepeptide-1 (GLP-1)/ gastric inhibitory polypeptide (GIP) dual agonist, tirzepatide to alleviate DN in mice and its underlying mechanisms.
We investigated the reno-protective effect of semaglutide and tirzepatide in a mouse model of DN, an insulin-treated positive control group was also included. Indicators of diabetic kidney injury and oxidative stress biomarkers were also assessed. RNA-seq analysis of renal tissue was conducted to explore the potential mechanism of action of tirzepatide and in vitro cell experiments were performed to validate its pathway.
In DN mice, one-third the dose of tirzepatide was consistent with that of semaglutide in lowering glucose, body weight, and urine albumin-to-creatine ratio (UACR) and in improving antioxidative stress activities, while insulin treatment could not effectively restore the UACR. RNA-seq analysis revealed that the PI3K-AKT signaling pathway was significantly enriched after tirzepatide treatment compared with that in the DN model. Confirmatory experiments demonstrated that tirzepatide regulated oxidative stress and the PI3K-AKT pathway in mouse podocyte cell-5 cells exposed to high glucose. Further mechanistic validation suggested that the antioxidative activity of tirzepatide was reversed by PI3K inhibitor.
These findings expand the potential effects and mechanics of tirzepatide in the treatment of DN, which may provide a novel therapeutic approach and therapeutic target for DN treatment.
目前缺乏针对肾功能不可逆恶化的糖尿病肾病（DN）的有效治疗方法。在本研究中，我们旨在研究胰高血糖素样肽-1（GLP-1）/胃抑制多肽（GIP）双重激动剂替尔泊肽减轻小鼠DN的能力及其潜在机制。
我们在DN小鼠模型中研究了司美格鲁肽和替尔泊肽的肾脏保护作用，还纳入了胰岛素治疗的阳性对照组。还评估了糖尿病肾损伤指标和氧化应激生物标志物。对肾组织进行RNA测序分析以探索替尔泊肽的潜在作用机制，并进行体外细胞实验以验证其途径。
在DN小鼠中，三分之一剂量的替尔泊肽在降低血糖、体重和尿白蛋白与肌酐比值（UACR）以及改善抗氧化应激活性方面与司美格鲁肽相当，而胰岛素治疗不能有效恢复UACR。RNA测序分析显示，与DN模型相比，替尔泊肽治疗后PI3K-AKT信号通路显著富集。验证性实验表明，替尔泊肽在高糖环境下对小鼠足细胞-5细胞的氧化应激和PI3K-AKT通路有调节作用。进一步的机制验证表明，PI3K抑制剂可逆转替尔泊肽的抗氧化活性。
这些发现扩展了替尔泊肽在治疗DN方面的潜在作用和机制，可能为DN治疗提供一种新的治疗方法和治疗靶点。
