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Response to: Correspondence on ‘SGLT2 inhibitors alleviated podocyte damage in lupus nephritis by decreasing inflammation and enhancing autophagy’ by Zhao et al
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  1. Yuan-yuan Qi1,2,3
  1. 1 Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
  2. 2 Zhengzhou University, Zhengzhou, Henan, People's Republic of China
  3. 3 Laboratory of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, People's Republic of China
  1. Correspondence to Dr Yuan-yuan Qi, Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; qqyyiillyy{at}126.com

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We would like to thank Soler, Jacobs-Cachá and Anders1 for their interest in our work on sodium glucose cotransporter (SGLT) 2 inhibitors’ treatment in lupus nephritis (LN).2 We completely understand your concerns and share the same perplexity regarding the reduced total IgG and dsDNA levels by empagliflozin in animal experiments, as you do. Hypogammaglobulinaemia has not been reported in any trials of SGLT2 inhibitors, and the immunosuppressive effects cannot be explained so far. These questions are of utmost importance and warrant further experiments for clarification. Recently, immunological properties have been implicated for SGLT2 inhibitors and were summarised by Bendotti et al. 3 Canagliflozin, not dapagliflozin, can suppress T-cell function, making it a promising option for T-cell-mediated autoimmune diseases.4 5 This is due to the off-target effects of canagliflozin, and dapagliflozin or empagliflozin have no known off-target effects. Empagliflozin, the one we used in our study, was reported capable of inhibiting CD4+ T cell proliferation and acting on macrophages. Considering the limited and preliminary studies SGLT2 inhibitors on the immune system, we acknowledge the necessity for in-depth research to reveal the underlying mechanisms.

Soler, Cacha and Anders also showed concerns regarding the expression of SGLT2 in podocytes. The expression of SGLT2 can also be detected in the podocytes of Alport mice and mice with protein overload-induced proteinuria by immunofluorescence staining.6 7 We also observed SGLT2 expression in the proximal tubules, as demonstrated in the Results section. We obtained images of immunofluorescence staining, mainly focused on the glomerulus at greater magnifications to show the expression of SGLT2 in podocytes in figure 2A,C. Moreover, our immunohistochemistry results demonstrated the expression of SGLT2 in both podocytes and tubules at lower magnifications (figure 2B,D). Very weak SGLT2 expression was detected by Western blotting using the human podocyte cell line, as shown in figure 3B (untreated group). After stimulation with IgG extracted from patients with lupus nephritis (IgG-LN), the expression of SGLT2 was significantly increased. It has been reported that the expression of SGLT2 is significantly increased in podocytes exposed to albumin via NF-κB signalling.7 IgG from patients with LN can also activate NF-κB in cultured human podocyte cell lines.8 The increased expression of SGLT2 under stimulation with IgG-LN is possibly related to NF-κB pathway activation. In view of the low SGLT2 expression levels in podocytes, the knockout of SGLT2 expression by the CRISPR/Cas9 system was tested after exposure to IgG-LN. We apologise for the oversight in omitting this description in figure 4A.

Regarding the expression of NLRP3 in podocytes, we appreciate the insights provided by Soler, Cacha and Anders. To date, the expression of NLRP3 has been detected in podocytes in many studies by immunohistochemical staining and Western blotting, and the activation of the NLRP3 inflammasome in podocytes has been reported to be involved in different kidney diseases, such as diabetic nephropathy,9 APOL1-associated podocytopathy10 and LN.11 Given the complexity of the cellular composition of kidney tissues, it is hard to distinguish resident mononuclear phagocytes in figure 4 as mentioned without immunohistochemical staining for specific biomarkers. Overall, we believe that your research on NLRP3 in podocytes is important.12 It will have a substantial impact on a considerable body of ongoing research and published studies.

We appreciate the attention given to our work and welcome further collaborations. The results of our study revealed reduced levels of proteinuria and serum creatinine and improved renal pathological alterations in MRL/lpr mice treated with empagliflozin. Further in vitro experiments showed that empagliflozin could protect podocytes from the damage induced by IgG extracted from patients with LN by attenuating inflammation and enhancing autophagy. Decreased levels of proteinuria were also observed in five patients with LN treated with empagliflozin.13 The cytoprotective, anti-inflammatory and autophagy-enhancing effects of SGLT2 inhibitors have been reported to contribute to decreased proteinuria and ameliorated renal pathology in several animal models of chronic kidney disease. In addition to improved kidney damage, we also observed a decrease in dsDNA and IgG levels. We presented the results with caution, understanding the complexity of lupus and the need for further validation in different lupus models. What is more, the findings from animal studies should be interpreted with caution and results may not always be confirmed in patients. Clinical trials and in vitro studies focused on immune system are necessary to verify the insights gained from animal models.

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Acknowledgments

I express my sincere appreciation to everyone who has shown interest in our research.

References

Footnotes

  • Handling editor Josef S Smolen

  • Contributors None.

  • Funding The authors have not declared a specific grant for this research from any funding agency in the public, commercial or not-for-profit sectors.

  • Competing interests None declared.

  • Provenance and peer review Commissioned; externally peer reviewed.

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