Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Zhengzhou University, Zhengzhou, Henan, China.
Ann Rheum Dis. 2023 Oct;82(10):1328-1340. doi: 10.1136/ard-2023-224242. Epub 2023 Jul 24.
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.
We applied empagliflozin treatment to lupus-prone MRL/ 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.
In MRL/ 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/ 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.
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.
在伴有 2 型糖尿病的患者中，大型心血管结局试验揭示了钠-葡萄糖共转运蛋白 2（SGLT2）抑制剂在肾脏结局方面的保护作用。然而，SGLT2 抑制剂对狼疮肾炎（LN）及其潜在机制的影响尚不清楚。
我们应用恩格列净治疗狼疮易感 MRL/小鼠，以探索 SGLT2 抑制剂的肾脏保护潜力。使用 CRISPR/Cas9 系统生成 SGLT2 敲除单克隆足细胞细胞系，以检查细胞和分子机制。
在接受恩格列净治疗的 MRL/小鼠中，鼠抗 dsDNA IgG 特异性抗体、血清肌酐和蛋白尿水平显著降低。对于肾脏病理评估，恩格列净给药减轻了肾小球和肾小管间质损伤。LN 患者和肾炎 MRL/小鼠的肾活检样本中 SGLT2 表达水平升高，与 synaptopodin 减少相关。SGLT2 抑制剂恩格列净通过减弱炎症和降低 mTORC1 活性增强自噬，从而减轻足细胞损伤。9 例接受 SGLT2 抑制剂治疗超过 2 个月的 LN 患者显示，使用 SGLT2 抑制剂可使蛋白尿从 29.6%显著降低至 96.3%。此外，在使用 SGLT2 抑制剂治疗期间，估计肾小球滤过率（eGFR）相对稳定。
本研究证实了 SGLT2 抑制剂在狼疮小鼠中的肾脏保护作用，为改善经典自身免疫性肾脏疾病（如 LN）的肾功能的非免疫抑制治疗提供了更多证据。
