Empagliflozin suppresses inflammation and protects against acute septic renal injury

Abstract

Background

Sepsis-induced systemic inflammation response syndrome is the leading cause of morbidity and mortality among patients in intensive care units in North America. While sepsis is associated with multiple organ damage, acute renal injury represents a hallmark of sepsis. Since systemic and renal inflammation is known to play a vital role in morbidity and mortality associated with sepsis, identifying a potent anti-inflammatory agent may help minimize morbidity and mortality associated with acute septic kidney injury. Since recent work has suggested that empagliflozin, a renal sodium-glucose cotransporter 2 (SGLT2) inhibitor, may assist in the treatment of inflammatory diseases, our objective was to examine the effect of empagliflozin on acute sepsis-induced renal injury.

Method

Mice were treated with three daily doses of empagliflozin or vehicle, with lipopolysaccharide (LPS) administered on the third day, at the same time as the third dose of empagliflozin or vehicle. In another cohort, mice were injected with a single dose of LPS 3 h before a dose of empagliflozin.

Results

Our results show that empagliflozin improves survival in a mouse model of LPS-induced septic shock. We further demonstrate that the beneficial effects of empagliflozin are likely mediated via reducing LPS-induced acute renal injury. Moreover, our data indicate that empagliflozin significantly reduces systemic and renal inflammation to contribute to the improvements observed in an LPS-model of acute septic renal injury.

Conclusion

Overall, the findings of this study suggest that empagliflozin could be repurposed to reduce morbidity and mortality in patients with acute septic renal injury.

Trial registration

Not applicable.

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Data availability

The data used or analyzed during this study are included in this article and available from the corresponding author upon reasonable request.

Abbreviations

BUN:

Blood urea nitrogen

Cas-1:

Caspase-1

Col:

Collagen

DAPI:

4′,6-Diamidino-2-phenylindole

DMSO:

Dimethyl sulfoxide

H&E:

Haematoxylin and eosin

IL:

Interleukin

INF-γ:

Interferon gamma

IP10:

Interferon gamma-induced protein 10

KUN:

Kidney urea nitrogen

LPS:

Lipopolysaccharide

LIF:

Leukemia inhibitory factor

MIG:

Monokine induced by gamma interferon

NLRP3:

Nucleotide-Binding Domain-Like Receptor Protein 3

SGLT2:

Sodium-Glucose Cotransporter 2

PBS:

Phosphate buffered saline

TNF-α:

Tumor necrosis factor-α

Tlr4:

Toll-like receptor 4

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Funding

This work was supported by a grant from the Canadian Institutes of Health Research (CIHR) to JRBD. JRBD is a Canada Research Chair in Molecular Medicine. This financing grant enabled the purchase of all reagents and materials used in the study. ZHM is the recipient of the Alberta Innovates Health Solution post-doctoral and CIHR fellowship awards. These fellowships made it possible to dedicate himself to the design of the study and collection, analysis, and interpretation of data and in writing the manuscript.

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Contributions

All authors have read and approved the manuscript. Participated in research design: ZHM, MF, ST, JRBD. Conducted experiments: ZHM, MF, ST. Performed data analysis: ZHM, MF, ST, JRBD. Wrote or contributed to the writing of the manuscript: ZHM, MF, ST, SS, JRBD. ZHM, MF, ST contributed equally to this work.

Corresponding author

Correspondence to Jason R. B. Dyck.

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Conflict of interest

The authors declare no competing interests.

Ethical approval

All animal procedures were approved by the University of Alberta Institutional Animal Care and Use Committee (Health Sciences 2 Committee; Approval Date: October 7, 2019; Number: AUP00000247), which conforms to the Guide for the Care and Use of Laboratory Animals published by the United States National Institutes of Health and the principles for biomedical research involving animals developed by the Council for International Organizations of Medical Sciences.

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Cite this article

Maayah, Z.H., Ferdaoussi, M., Takahara, S. et al. Empagliflozin suppresses inflammation and protects against acute septic renal injury. Inflammopharmacol (2020). https://doi.org/10.1007/s10787-020-00732-4

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Keywords

  • Empagliflozin
  • Inflammation
  • Sepsis
  • Renal injury