Li Ran, She Dunmin, Ye Zhengqin, Fang Ping, Zong Guannan, Zhao Yong, Hu Kerong, Zhang Liya, Lei Sha, Zhang Keqin, Xue Ying
Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, People's Republic of China.
Department of Endocrinology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, 225001, People's Republic of China.
Diabetes Metab Syndr Obes. 2022 Apr 29;15:1331-1345. doi: 10.2147/DMSO.S353717. eCollection 2022.
This study aims to investigate the renal protective effect of glucagon-like peptide 1 receptor agonist (GLP-1RA) on improving renal tubular damage in diabetic kidney disease (DKD) and to explore the potential mechanism of GLP-1RA on renal tubular protection.
Long-acting GLP-1RA was used to treat DKD mice for 12 weeks. The label-free quantitative proteomic analysis of renal proteins was conducted to explore the differentially expressed proteins (DEPs) in the renal tissues of the control, DKD and GLP-1RA groups. The DEPs and markers of renal tubular injury were verified by qPCR in vivo and in vitro. The expression of glucagon-likepeptide-1 receptor (GLP-1R) in renal tubules was determined by immunofluorescence staining.
GLP-1RA treatment significantly improved the tubular damages in kidney tissues of DKD mice and mTEC cells stimulated by high glucose (HG). Proteomics analysis revealed that 30 proteins in kidney tissue were differentially expressed among three groups. Seminal vesicle secretory protein 6 (SVS6) was the most differentially expressed protein in kidney tissues among three groups of mice. The expression changes of mRNA in vitro and in vivo detected by qPCR were consistent with the results of proteomic analysis. Furthermore, reduction of expression by SVS6 siRNA could attenuate HG-stimulated tubular injury in mTEC cells. Immunofluorescence staining also found that GLP-1R was widely expressed in renal tubules in vitro and in vivo.
GLP-1RA significantly improved renal tubular damage in DKD mice. SVS6 may be a potential therapeutic target for GLP-1RA in the treatment of DKD.
本研究旨在探讨胰高血糖素样肽1受体激动剂（GLP-1RA）对改善糖尿病肾病（DKD）肾小管损伤的肾脏保护作用，并探索GLP-1RA肾小管保护的潜在机制。
使用长效GLP-1RA治疗DKD小鼠12周。对肾脏蛋白质进行无标记定量蛋白质组学分析，以探索对照组、DKD组和GLP-1RA组肾组织中差异表达蛋白（DEPs）。通过体内和体外qPCR验证DEPs和肾小管损伤标志物。通过免疫荧光染色测定肾小管中胰高血糖素样肽-1受体（GLP-1R）的表达。
GLP-1RA治疗显著改善了DKD小鼠肾组织和高糖（HG）刺激的小鼠肾小管上皮细胞（mTEC）中的肾小管损伤。蛋白质组学分析显示，三组肾组织中有30种蛋白质差异表达。精囊分泌蛋白6（SVS6）是三组小鼠肾组织中差异表达最明显的蛋白质。qPCR检测的体内和体外mRNA表达变化与蛋白质组学分析结果一致。此外，SVS6 siRNA降低其表达可减轻HG刺激的mTEC细胞肾小管损伤。免疫荧光染色还发现，GLP-1R在体内和体外肾小管中广泛表达。
GLP-1RA显著改善了DKD小鼠的肾小管损伤。SVS6可能是GLP-1RA治疗DKD的潜在治疗靶点。
