SGLT2 inhibitors alleviated podocyte damage in lupus nephritis by decreasing inflammation and enhancing autophagy

医学 狼疮性肾炎 足细胞 自噬 肾炎 系统性红斑狼疮 炎症 免疫学 内科学 蛋白尿 疾病 细胞凋亡 生物化学 化学
作者
Xinyu Zhao,Shuangshuang Li,Ying-xin He,Lijie Yan,Fu Lv,Qi-meng Liang,Yu-hui Gan,Li-pei Han,Hongde Xu,Yongchun Li,Yuanyuan Qi
出处
期刊:Annals of the Rheumatic Diseases [BMJ]
卷期号:82 (10): 1328-1340 被引量:31
标识
DOI:10.1136/ard-2023-224242
摘要

Objectives The protective role of sodium glucose cotransporter 2 (SGLT2) inhibitors in renal outcomes has been revealed by large cardiovascular outcome trials among patients with type 2 diabetes. However, the effect of SGLT2 inhibitors on lupus nephritis (LN) and its underlying mechanisms remain unknown. Methods We applied empagliflozin treatment to lupus-prone MRL/ lpr mice to explore the renal protective potential of SGLT2 inhibitors. An SGLT2 knockout monoclonal podocyte cell line was generated using the CRISPR/Cas9 system to examine the cellular and molecular mechanisms. Results In MRL/ lpr mice treated with empagliflozin, the levels of mouse anti-dsDNA IgG-specific antibodies, serum creatinine and proteinuria were markedly decreased. For renal pathology assessment, both the glomerular and tubulointerstitial damages were lessened by administration of empagliflozin. The levels of SGLT2 expression were increased and colocalised with decreased synaptopodin in the renal biopsy samples from patients with LN and MRL/ lpr mice with nephritis. The SGLT2 inhibitor empagliflozin could alleviated podocyte injury by attenuating inflammation and enhanced autophagy by reducing mTORC1 activity. Nine patients with LN treated with SGLT2 inhibitors with more than 2 months of follow-up showed that the use of SGLT2 inhibitors was associated with a significant decrease in proteinuria from 29.6% to 96.3%. Moreover, the estimated glomerular filtration rate (eGFR) was relatively stable during the treatment with SGLT2 inhibitors. Conclusion This study confirmed the renoprotective effect of SGLT2 inhibitors in lupus mice, providing more evidence for non-immunosuppressive therapies to improve renal function in classic autoimmune kidney diseases such as LN.
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