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Inhibition of tumor necrosis factor-α enhanced the antifibrotic effect of empagliflozin in an animal model with renal insulin resistance

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Abstract

Insulin resistance (IR) has emerged as one of the main risk factors for renal fibrosis (RF) that represents a common stage in almost all chronic kidney disease. The present study aims to investigate the inhibitory effect of empagliflozin (EMPA “a sodium-glucose co-transporter 2 inhibitor”) and infliximab [IFX “a tumor necrosis factor-α (TNF-α) antibody”] on RF in rats with induced IR. IR was induced by adding 10% fructose in drinking water for 20 weeks. Thereafter, fructose-induced IR rats were concurrently treated with EMPA (30 mg/kg), IFX (1 dose 5 mg/kg), or EMPA + IFX for 4 weeks, in addition to IR control group (received 10% fructose in water) and normal control (NC) group. Rats with IR displayed hyperglycemia, deterioration in kidney functions, glomerulosclerosis, and collagen fiber deposition in renal tissues as compared to NC. This was associated with downregulation of the renal sirtuin 1 (Sirt 1) expression along with higher renal tissue TNF-α and transforming growth factor-β1 (TGF-β1) levels. Both EMPA and IFX significantly modulated the aforementioned fibrotic cytokines, upregulated the renal Sirt 1 expression, and attenuated RF compared to IR control group. Of note, IFX effect was superior to that of EMPA. However, the combination of EMPA and IFX alleviated RF to a greater extent surpassing the monotherapy. This may be attributed to the further upregulation of renal Sirt 1 in addition to the downregulation of fibrotic cytokines. These findings suggest that the combination of EMPA and IFX offers additional benefits and may represent a promising therapeutic option for RF.

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Authors and Affiliations

  1. Department of Biochemistry, Faculty of Pharmacy, Zagazig University, Zagazig, Egypt

    Hoda E. Mohamed, Mervat E. Asker & Yasmin K. Mahmoud

  2. Nephrology Division, Department of Internal Medicine, Faculty of Medicine, Suez Canal University, Ismailia, Egypt

    Mohammed M. Keshawy

  3. Department of Histology, Faculty of Medicine for Girls, Al-Azhar University, Cairo, Egypt

    Rehab A. Hasan

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  1. Hoda E. Mohamed
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Contributions

HM: conception and design of the research, revision of the manuscript, and gave final approval. MA: conception and design of the research, revision of the manuscript, and gave final approval. MK: data analysis, interpretation of results, and manuscript editing. RH: carried out the histological examination. YM: carried out the experiments, data analysis, interpretation of results, and writing the drafted manuscript. All authors revised and approved the final manuscript for submission.

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Correspondence to Hoda E. Mohamed.

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Mohamed, H.E., Asker, M.E., Keshawy, M.M. et al. Inhibition of tumor necrosis factor-α enhanced the antifibrotic effect of empagliflozin in an animal model with renal insulin resistance. Mol Cell Biochem 466, 45–54 (2020). https://doi.org/10.1007/s11010-020-03686-x

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