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Empagliflozin protective effects against cisplatin-induced acute nephrotoxicity by interfering with oxidative stress and inflammation in Wistar rats

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Abstract

Cisplatin (Cis) is a platinum-based antineoplastic drug used in various types of cancers. This drug can induce nephrotoxicity as a cause of acute kidney injury (AKI) by inducing oxidative stress and inflammation. Empagliflozin (Empa) is a newly developed inhibitor of sodium-glucose cotransporter-2 (SGLT2) approved as an antidiabetic medication for patients with type 2 diabetes mellitus. In addition to its blood glucose-lowering effect, Empa has been shown to exert anti-inflammatory and anti-oxidant properties. The current study aimed to investigate the protective effects of Empa on Cis-induced nephrotoxicity in rats. Male Wistar albino rats were divided into five groups, each of six rats: Sham group (received vehicle for 7 days), Control group (received vehicle for 7 days and Cis injection on day 2), Cis + Empa10 (received 10mg/kg Empa for 7 days and Cis injection on day 2), Cis + Empa30 (received 30mg/kg Empa for 7 days and Cis injection on day 2) and, Empa 30 (received 30mg/kg Empa for 7 days). One day after the last injection in each group, rats were weighed and then sacrificed to analyze the hematological, biochemical, and histological parameters. Cis markedly increased levels of inflammatory parameters such as renal tumor necrosis factor-alpha (TNF-α), interleukin (IL)-1β, and myeloperoxidase (MPO) activity. Notably, malondialdehyde (MDA), blood urea nitrogen (BUN), and creatinine levels were enhanced after Cis administration. Also, the chemotherapeutic agent significantly reduced antioxidant indicators such as renal catalase (CAT), glutathione peroxidase (GpX), and superoxide dismutase (SOD). Furthermore, histopathological examinations also revealed severe renal damage following Cis treatment which was improved by Empa administration. Empa treatment at both doses (10 mg/kg and 30 mg/kg) reversed Cis-induced changes in all the above renal parameters. In conclusion, Empa has protective effects on Cis-induced nephrotoxicity by inhibition of oxidative stress and inflammation.

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Data availability

No datasets were generated or analysed during the current study.

Abbreviations

Cis:

Cisplatin

FDA:

Food and Drug Administration

AKI:

Acute kidney injury

TNF:

Tumor necrosis factor

MCP:

Monocyte chemoattractant protein

ICAM:

Intercellular adhesion molecule

TLR:

Toll-like receptor

ROS:

Reactive oxygen species

SGLT2I:

Sodium-glucose transporter 2 inhibitor

COX:

Cyclooxygenase

iNOS:

Inducible nitric oxide synthase

NF-κB:

Nuclear factor kappa betta

JNK:

c-Jun N-terminal kinases

JAK/STAT:

Janus kinase/signal transducers and transcription

GSH:

Glutathione

SOD:

Superoxide dismutase

IL:

Interleukin

MDA:

Malondialdehyde

CAT:

Catalase

GpX:

Glutathione peroxidase

BUN:

Blood urea nitrogen

DMSO:

Dimethyl sulfoxide

IP:

Intraperitoneal

H&E:

Hematoxylin and eosin

ATN:

Acute tubular necrosis

SEM:

Standard error of the mean

ANOVA:

Analysis of variance 

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Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Author information

Author notes

  1. Nika Farrokh-Eslamlou and Saeideh Momtaz contributed equally in this paper.

Authors and Affiliations

  1. Department of Toxicology & Pharmacology, Faculty of Pharmacy, Tehran Medical Sciences, Islamic Azad University, No. 99, Yakhchal, Gholhak, Shariati St., P. O. Box: 19419-33111, Tehran, Iran

    Nika Farrokh-Eslamlou, Amirhossein Niknejad, Yasamin Hosseini & Amir Hossein Abdolghaffari

  2. GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran

    Nika Farrokh-Eslamlou, Amirhossein Niknejad, Yasamin Hosseini & Amir Hossein Abdolghaffari

  3. Medicinal Plants Research Center, Institute of Medicinal Plants, ACECR, Karaj, Iran

    Saeideh Momtaz

  4. Department of Toxicology and Pharmacology, School of Pharmacy, and Toxicology and Diseases Group, Pharmaceutical Sciences Research Center (PSRC), The Institute of Pharmaceutical Sciences (TIPS), Tehran University of Medical Sciences, Tehran, Iran

    Saeideh Momtaz

  5. Department of Pharmaceutics, Faculty of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran

    Parvin Mahdaviani

  6. Department of Pharmacology and Toxicology, Faculty of Pharmacy, Urmia University of Medical Sciences, Sero Road, Urmia, 5715799313, Iran

    Morteza Ghasemnejad-Berenji

Authors
  1. Nika Farrokh-Eslamlou
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  4. Yasamin Hosseini
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Contributions

Morteza Ghasemnejad-Berenji and Amir Hossein Abdolghaffari contributed to the study conception and design. Animal treatment and analysis were performed by Nika Farrokh-Eslamlou. The first draft of the manuscript was written by Saeideh Momtaz, Amirhossein Niknejad and Yasamin Hosseini. Saeideh Momtaz and Parvin Mahdaviani edited the draft. All authors read and approved the final manuscript. The authors declare that all data were generated in-house and that no paper mill was used.

Corresponding authors

Correspondence to Morteza Ghasemnejad-Berenji or Amir Hossein Abdolghaffari.

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Ethics approval

Approval was obtained from the ethics committee of Islamic Azad university, Pharmaceutical Branch (IR.IAU.PS.REC.1401.195) and performed in complete accordance with the Guide for the Care and Use of Laboratory Animals (NIH publication No 85–23, National Academy Press, Washington, DC, USA, revised 1996).

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Farrokh-Eslamlou, N., Momtaz, S., Niknejad, A. et al. Empagliflozin protective effects against cisplatin-induced acute nephrotoxicity by interfering with oxidative stress and inflammation in Wistar rats. Naunyn-Schmiedeberg's Arch Pharmacol (2024). https://doi.org/10.1007/s00210-024-03088-6

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