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Empagliflozin, SGLT2 inhibitor, attenuates renal fibrosis in rats exposed to unilateral ureteric obstruction: potential role of klotho expression

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Abstract

Chronic kidney disease (CKD) is a global healthcare problem; however until now, there is no effective treatment that can stop its progression. In this study, we aimed to investigate the effect of empagliflozin, a sodium-glucose linked transporter-2 inhibitor (SGLT2I) in a model of unilateral ureteric obstruction (UUO) in rats, as a model of progressive renal interstitial fibrosis in vivo and the possibility of inclusion of klotho protein. Rats were randomly divided into five groups: group 1: control group, group 2: UUO untreated group, group 3: prophylactic SGLT2I treatment before UUO, group 4: immediate SGLT2I treatment after UUO, and group 5: delayed SGLT2I treatment (this group received distilled water 1 week after UUO then empagliflozin for 2 weeks). At the end of the experiment period, animals were sacrificed, and kidney fibrotic and inflammatory parameters were measured. Also kidney sections were examined histopathologically for CTGF expression. UUO resulted in renal dysfunction and fibrosis through upregulating inflammatory cascade (NF-κB-TLR4) as well as many fibrotic pathways (as TGF-β1, αSMA, Wnt, CTGF, and fibronectin) with significant reduction in the klotho protein expression. We hypothesized that both prophylactic and immediate treatment with empagliflozin after UUO in rats exert more renoprotective effect in comparison with delayed treatment via enhancement of renal klotho expression and activity, for further investigations.

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Abbreviations

SGLT2I:

Sodium-glucose linked transponter-2 inhibitors

UUO:

Unilateral ureteric obstruction

TNF-α:

Tumor necrosis factor-α

TGF-β1 :

Transforming growth factor beta

NF-κB:

Nuclear factor κB

TLR4:

Toll-like receptor-4

α-SMA:

Alpha-smooth muscle actin

CTGF:

Connective tissue growth factor

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Acknowledgments

The authors thank the associate prof. Hayam Rashed, associate prof. of pathology, Zagazig University Egypt, for his kind help in histopathological examination.

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Authors and Affiliations

  1. Department of Clinical Pharmacology, Faculty of Medicine, Zagazig University, Zagazig, 44519, Egypt

    Noha A. T. Abbas & Amal El. Salem

  2. Department of Internal Medicine, Endocrinology Division, Faculty of Medicine, Zagazig University, Zagazig, Egypt

    Mohammed M. Awad

Authors
  1. Noha A. T. Abbas
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  2. Amal El. Salem
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  3. Mohammed M. Awad
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Contributions

Noha A.T. Abbas, Mohammed M. Awad, and Amal El. Salem designed experiments. Noha A. T. Abbas and Amal El. Salem performed the experiments. Noha A. T. Abbas and Amal El. Salem wrote the paper. Mohammed M. Awad  revised and finalized the manuscript.

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Correspondence to Noha A. T. Abbas.

Ethics declarations

All experimental protocols were approved by the ethics committee of Zagazig University. The study was approved by the local Animal Ethical Committee of Zagazig University, Egypt. All experimental procedures were carried out in accordance with the guidelines set forth by the National Institutes of Health (USA).

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The authors declare that they have no competing interests.

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Abbas, N.A.T., El. Salem, A. & Awad, M.M. Empagliflozin, SGLT2 inhibitor, attenuates renal fibrosis in rats exposed to unilateral ureteric obstruction: potential role of klotho expression. Naunyn-Schmiedeberg's Arch Pharmacol 391, 1347–1360 (2018). https://doi.org/10.1007/s00210-018-1544-y

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