Deng Fengyi, Zhang Ping, Li Huaiyun, Fan Xingyu, Du Yijun, Zhong Xing, Wang Nuojin, He Meiwen, Wang Yue, Pan Tianrong
Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei 230601, Anhui Province, China; Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei 230601, Anhui Province, China.
Department of Endocrinology, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei 230601, Anhui Province, China; Research Center for Translational Medicine, The Second Affiliated Hospital of Anhui Medical University, No. 678 Furong Road, Jingkai District, Hefei 230601, Anhui Province, China.
Cell Signal. 2025 Mar;127:111603. doi: 10.1016/j.cellsig.2025.111603. Epub 2025 Jan 11.
Diabetic kidney disease (DKD), a microvascular complication of diabetes mellitus, represents a significant clinical challenge. This study investigated the reno-protective effects of dulaglutide, a glucagon-like peptide-1 receptor agonist (GLP-1 RA) widely used in the management of diabetes, and aimed to elucidate its underlying mechanisms. Mice with db/db and db/m genotypes were allocated into four experimental groups and treated with either dulaglutide or a saline control for 10 weeks. Following the treatment period, biological samples were collected for comprehensive analysis. Serum and urinary creatinine levels were measured using a creatinine assay, while urinary protein concentrations were quantified via ELISA. Histopathological kidney damage was assessed through hematoxylin and eosin (HE) staining, with glomerular lesions evaluated using periodic acid-Schiff (PAS) staining. Inflammatory markers, ferroptosis-related indicators, and fibrosis in kidney tissues were further analyzed through PCR, Western blot (WB), immunohistochemistry (IHC), and transmission electron microscopy (TEM). Consistent with prior findings, this research demonstrated that dulaglutide improves renal function and mitigates pathological kidney damage in db/db mice. Treatment with dulaglutide significantly reduced mRNA expression of ferroptosis-related markers, including ACSL4, SLC7A11, and Ptgs2, alongside a decrease in 4-HNE levels in kidney tissues. Furthermore, dulaglutide downregulated ACSL4 protein levels and upregulated GPX4 protein expression, thereby ameliorating mitochondrial damage in renal tubular cells. In addition to these effects, dulaglutide alleviated kidney inflammation and fibrosis in db/db mice, with concomitant suppression of P-STAT3 and P-ERK expression. Collectively, these findings underscore dulaglutide's reno-protective effects in DKD, mediated through the inhibition of inflammation, improvement in renal fibrosis and ferroptosis, and modulation of P-STAT3 and P-ERK signaling pathways.
糖尿病肾病（DKD）是糖尿病的一种微血管并发症，是一项重大的临床挑战。本研究调查了度拉糖肽（一种广泛用于糖尿病管理的胰高血糖素样肽-1受体激动剂（GLP-1 RA））的肾脏保护作用，旨在阐明其潜在机制。将db/db和db/m基因型的小鼠分为四个实验组，分别用度拉糖肽或生理盐水对照处理10周。治疗期结束后，收集生物样本进行综合分析。使用肌酐测定法测量血清和尿肌酐水平，通过ELISA定量尿蛋白浓度。通过苏木精和伊红（HE）染色评估肾脏组织病理学损伤，使用过碘酸希夫（PAS）染色评估肾小球病变。通过PCR、蛋白质免疫印迹（WB）、免疫组织化学（IHC）和透射电子显微镜（TEM）进一步分析肾脏组织中的炎症标志物、铁死亡相关指标和纤维化情况。与先前的研究结果一致，本研究表明度拉糖肽可改善db/db小鼠的肾功能并减轻病理性肾损伤。度拉糖肽治疗显著降低了铁死亡相关标志物（包括ACSL4、SLC7A11和Ptgs2）的mRNA表达，同时肾脏组织中4-HNE水平降低。此外，度拉糖肽下调了ACSL4蛋白水平并上调了GPX4蛋白表达，从而改善了肾小管细胞中的线粒体损伤。除了这些作用外，度拉糖肽还减轻了db/db小鼠的肾脏炎症和纤维化，同时抑制了P-STAT3和P-ERK表达。总的来说，这些发现强调了度拉糖肽在DKD中的肾脏保护作用，其作用机制是通过抑制炎症、改善肾纤维化和铁死亡以及调节P-STAT3和P-ERK信号通路来实现的。
