Formononetin Ameliorates Renal Dysfunction, Oxidative Stress, Inflammation, and Apoptosis and Upregulates Nrf2/HO-1 Signaling in a Rat Model of Gentamicin-Induced Nephrotoxicity

Osama Y Althunibat; Mohammad H Abukhalil; Saleem H Aladaileh; Haitham Qaralleh; Wesam Al-Amarat; Manal A Alfwuaires; Abdulmohsen I Algefare; Nader Ibrahim Namazi; Sahar J Melebary; Ahmad O Babalghith; Carlos Adam Conte-Junior

doi:10.3389/fphar.2022.916732

Formononetin Ameliorates Renal Dysfunction, Oxidative Stress, Inflammation, and Apoptosis and Upregulates Nrf2/HO-1 Signaling in a Rat Model of Gentamicin-Induced Nephrotoxicity

Front Pharmacol. 2022 May 26:13:916732. doi: 10.3389/fphar.2022.916732. eCollection 2022.

Affiliations

¹ Department of Medical Analysis, Princess Aisha Bint Al-Hussein College of Nursing and Health Sciences, Al-Hussein Bin Talal University, Ma'an, Jordan.
² Department of Biology, College of Science, Al-Hussein Bin Talal University, Ma'an, Jordan.
³ Department of Medical Laboratory Sciences, Mutah University, Karak, Jordan.
⁴ Department of Medical Support, Al-karak University College, Al-Balqa' Applied University, As-Salt, Jordan.
⁵ Department of Biological Sciences, Faculty of Science, King Faisal University, Al-Ahsa, Saudi Arabia.
⁶ Pharmaceutics and Pharmaceutical Technology Department, College of Pharmacy, Taibah University, Al Madinah Al Munawarah, Saudi Arabia.
⁷ Department of Biology, College of Science, University of Jeddah, Jeddah, Saudi Arabia.
⁸ Medical Genetics Department, College of Medicine, Umm al-qura University, Makkah, Saudi Arabia.
⁹ Center for Food Analysis (NAL), Technological Development Support Laboratory (LADETEC), Federal University of Rio de Janeiro (UFRJ), Rio de Janeiro, Brazil.

Abstract

Gentamicin (GEN) is a bactericidal aminoglycoside known to cause nephrotoxicity. Formononetin (FN) is a potent flavonoid that exhibits numerous promising pharmacological activities. In this study, we have assessed the nephroprotective efficacy of FN against GEN-induced renal injury in rats. Rats were orally administered with FN (60 mg/kg/day, for 2 weeks) and were co-treated with intraperitoneal (i.p.) injection of GEN (100 mg/kg/day) during the days 8-14. GEN-treated rats demonstrated increased urea and creatinine levels in serum associated with marked histopathological changes in the kidney. Malondialdehyde (MDA) and protein carbonyl contents were elevated, whereas glutathione concentration and catalase and superoxide dismutase activities were lowered in GEN-administered rats. The FN largely prevented tissue damage, attenuated renal function, reduced MDA and protein carbonyl, and enhanced antioxidant capacity in the kidney of GEN-administrated animals. The kidney of GEN-treated rats demonstrated elevated Bax and caspase-3 protein expression, accompanied by lowered Bcl-2 protein expression, an effect that FN attenuated. Moreover, FN treatment caused upregulation of nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase 1 (HO-1) expression in renal tissue of GEN-intoxicated animals. Collectively, FN protects against GEN-caused renal damage via exhibiting antioxidant, anti-inflammatory, and antiapoptotic activities and augmenting Nrf2 signaling, suggesting FN as a promising agent for preventing drug-induced organ damage.

Keywords: Nrf2; formononetin; gentamicin; inflammation; nephrotoxicity; oxidative stress.