The Protective Effects of Alpha-Tocopherol Against Gentamicin-Induced Nephrotoxicity: The Potential Role of the Nrf2/NQO1 Pathway

Ashrafi, Soroush; Heidari, Reza; Ashrafi, Mohammad Reza; Chamanara, Mohsen; Dadpay, Masoomeh; Ebrahimi, Mohsen

doi:10.30491/jabr.2024.426639.1691

The Protective Effects of Alpha-Tocopherol Against Gentamicin-Induced Nephrotoxicity: The Potential Role of the Nrf2/NQO1 Pathway

Document Type : Original Article

Authors

Soroush Ashrafi ¹

Reza Heidari ²

Mohammad Reza Ashrafi ³

Mohsen Chamanara ¹^{, 4}

Masoomeh Dadpay ⁵

Mohsen Ebrahimi ¹^{, 4}

¹ Department of Toxicology and Pharmacology, Faculty of Medicine, AJA University of Medical Sciences, Tehran, Iran

² Medical Biotechnology Research Center, AJA University of Medical Sciences, Tehran, Iran

³ Department of Physiology, School of Medicine, Arak University of Medical Sciences, Arak, Iran

⁴ Toxicology Research Center, AJA University of Medical Sciences, Tehran, Iran

⁵ Department of Pathology, AJA University of Medical Sciences, Tehran, Iran

10.30491/jabr.2024.426639.1691

Abstract

Introduction: Aminoglycosides like gentamicin can cause nephrotoxicity by increasing reactive oxygen species (ROS) and reducing antioxidants. The transcription factor Nrf2 regulates antioxidant genes like NQO1 to combat oxidative stress. This study evaluated Nrf2/NQO1 involvement in gentamicin renal toxicity and vitamin E protection.
Materials and Methods: 24 rats were divided into control, gentamicin, vitamin E, and gentamicin plus vitamin E groups. Gentamicin (100 mg/kg) and vitamin E (250 mg/kg) were given intraperitoneally for 8 days. Kidney function, oxidative stress, Nrf2/NQO1 expression, and histology were analyzed.
Results: Gentamicin significantly increased serum creatinine by 1.98-fold (1.43 ± 0.49 vs 0.72 ± 0.16 mg/dl, p <0.01) and BUN by 5.58-fold (252.3 ± 78.13 vs 45.18 ± 7.26 mg/dl, p <0.0001) compared to control. Gentamicin also markedly suppressed renal Nrf2 mRNA expression by 83% and NQO1 by 79% versus control (p <0.0001). Vitamin E partially alleviated the functional impairment and downregulation of Nrf2 and NQO1 caused by gentamicin. The vitamin E group displayed the highest Nrf2 (2.8-fold vs control) and NQO1 (1.6-fold vs control) expression among all groups (p <0.0001).
Conclusions: Gentamicin appears to cause nephrotoxicity partly by suppressing Nrf2/NQO1 antioxidant defense. Vitamin E provided renoprotection by scavenging ROS and potentially reactivating Nrf2/NQO1. The study suggests oxidative stress is an important mechanism in aminoglycoside kidney toxicity that may be mitigated by appropriate antioxidants. Evaluating Nrf2/NQO1 modulation provides insights into gentamicin nephrotoxicity and related kidney injuries.

Keywords

Acute Kidney Injury,

Gentamicin

α-Tocopherol,

Nrf2,

NQO1