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Systemic lupus erythematosus
SGLT2 inhibitors alleviated podocyte damage in lupus nephritis by decreasing inflammation and enhancing autophagy
  1. Xin-yu Zhao1,2,
  2. Shuang-shuang Li1,2,3,4,
  3. Ying-xin He1,2,3,4,
  4. Li-jie Yan1,2,3,4,
  5. Fu Lv1,2,
  6. Qi-meng Liang1,2,
  7. Yu-hui Gan1,2,3,4,
  8. Li-pei Han1,2,
  9. Hong-de Xu2,4,
  10. Yong-chun Li2,4,
  11. Yuan-yuan Qi1,2,5
  1. 1 Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
  2. 2 Zhengzhou University, Zhengzhou, Henan, China
  3. 3 School of Pharmaceutical Sciences, Zhengzhou University, Zhengzhou, China
  4. 4 Ministry of Education of China, Institute of Drug Discovery and Development, Zhengzhou University, Zhengzhou, Henan, China
  5. 5 Laboratory of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou Henan, China
  1. Correspondence to Dr Yuan-yuan Qi, Department of Nephrology, 1. Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou Henan, 450052 P. R. China 2. Zhengzhou University, Zhengzhou Henan, 450001 P. R. China 3. Laboratory of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou Henan, 450052 P. R. China, Zhengzhou, Henan Province, China; qqyyiillyy{at}126.com

Abstract

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.

  • Lupus Nephritis
  • Lupus Erythematosus, Systemic
  • Inflammation

Data availability statement

Data are available upon reasonable request. The data that support the findings of this study are available from the corresponding author upon reasonable request.

https://doi.org/10.1136/ard-2023-224242

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    Data availability statement

    Data are available upon reasonable request. The data that support the findings of this study are available from the corresponding author upon reasonable request.

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    Footnotes

    • Handling editor Josef S Smolen

    • X-yZ, S-sL and Y-xH contributed equally.

    • Contributors Conceived and designed the experiment: Y-yQ; performed the animal experiments: S-sL, L-jY, Y-hG, L-pH, H-dX and Y-cL; performed the cell experiments: X-yZ, Y-xH and FL; collected and analysed the clinical information: X-yZ and Y-yQ; analysed the data: Y-yQ, X-yZ, S-sL, FL and Q-mL; interpretation of the finding: Y-yQ and X-yZ. All the authors contributed to writing the manuscript. Y-yQ is responsible for the overall content as guarantor.

    • Funding This work was supported by the National Science Foundation of China (grant number 81900643), the China Postdoctoral Science Foundation Grant (grant number 2019M652592), the Postdoctoral Research Grant in Henan Province (grant numbers 1902005 and 1901004) and the Scientific Research and Innovation Team of The First Affiliated Hospital of Zhengzhou University (grant number ZYCXTD2023009 and QNCXTD2023009). The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

    • Competing interests None declared.

    • Patient and public involvement Patients and/or the public were not involved in the design, conduct, reporting or dissemination plans of this research.

    • Provenance and peer review Not commissioned; externally peer reviewed.

    • Supplemental material This content has been supplied by the author(s). It has not been vetted by BMJ Publishing Group Limited (BMJ) and may not have been peer-reviewed. Any opinions or recommendations discussed are solely those of the author(s) and are not endorsed by BMJ. BMJ disclaims all liability and responsibility arising from any reliance placed on the content. Where the content includes any translated material, BMJ does not warrant the accuracy and reliability of the translations (including but not limited to local regulations, clinical guidelines, terminology, drug names and drug dosages), and is not responsible for any error and/or omissions arising from translation and adaptation or otherwise.