Glucagon-Like Peptide 1 Receptor Agonist Improves Renal Tubular Damage in Mice with Diabetic Kidney Disease

Ran Li; Dunmin She; Zhengqin Ye; Ping Fang; Guannan Zong; Yong Zhao; Kerong Hu; Liya Zhang; Sha Lei; Keqin Zhang; Ying Xue

doi:10.2147/DMSO.S353717

Glucagon-Like Peptide 1 Receptor Agonist Improves Renal Tubular Damage in Mice with Diabetic Kidney Disease

Diabetes Metab Syndr Obes. 2022 Apr 29:15:1331-1345. doi: 10.2147/DMSO.S353717. eCollection 2022.

Authors

Ran Li¹, Dunmin She², Zhengqin Ye¹, Ping Fang¹, Guannan Zong¹, Yong Zhao¹, Kerong Hu¹, Liya Zhang¹, Sha Lei¹, Keqin Zhang¹, Ying Xue¹

Affiliations

¹ Department of Endocrinology and Metabolism, Tongji Hospital, School of Medicine, Tongji University, Shanghai, 200065, People's Republic of China.
² Department of Endocrinology, Northern Jiangsu People's Hospital Affiliated to Yangzhou University, Yangzhou, Jiangsu, 225001, People's Republic of China.

Abstract

Purpose: 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.

Methods: 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.

Results: 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 Svs6 mRNA in vitro and in vivo detected by qPCR were consistent with the results of proteomic analysis. Furthermore, reduction of Svs6 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.

Conclusion: 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.

Keywords: diabetic kidney disease; glucagon-like peptide-1 receptor agonist; renal tubular injury; seminal vesicle secretory protein 6.

Grants and funding

This study was sponsored by the National Natural Science Foundation of China (Grant No. 81974105, 81670805, 81800705), Shanghai Pujiang Program (Grant No. 2019PJD050), Novo Nordisk China Diabetes Young Scientific Talent Research Funding, Psychosomatic Medicine Project of Key Developing Disciplines of Shanghai Municipal Health Commission (2019ZB0202), the Science and Technology Innovation Program of Shanghai (Grant No. 16411954700), Scientific research project of Shanghai Municipal Health Commission (Grant No. 20194Y0460), Cultivation project for National Natural Science Foundation of Shanghai Tongji Hospital, and Doctoral Fund of Northern Jiangsu Hospital (Grant No. BSQDJ0142).