Targeting KEAP1/Nrf2, AKT, and PPAR-γ signals as a potential protective mechanism of diosmin against gentamicin-induced nephrotoxicity

• Published in: Life sciences (1973) 2021-06, Vol.275, p.119349, Article 119349
• Main Authors: Ali, Fares E.M., Sayed, Ahmed M., El-Bahrawy, Ali H., Omar, Zainab M.M., Hassanein, Emad H.M.
• Format: Article
• Language: English
• Subjects: Acute Kidney Injury - chemically induced; Acute Kidney Injury - pathology; Acute Kidney Injury - prevention & control; AKT protein; Aminoglycoside antibiotics; Aminoglycosides; Animals; Antibiotics; Antioxidants; Blotting, Western; Creatinine - blood; Diosmin; Diosmin - pharmacology; Diosmin - therapeutic use; Down-regulation; Flavonoids; Gentamicin; Gentamicins - toxicity; Heme; Heme oxygenase (decyclizing); KEAP1/Nrf2/ARE; Kelch-Like ECH-Associated Protein 1 - metabolism; Kidney - drug effects; Kidney - pathology; Kidney diseases; Kidneys; Kinases; Male; NF-E2-Related Factor 2 - metabolism; Oncogene Protein v-akt - metabolism; Oxidants; Oxidizing agents; Oxygenase; P-AKT/AKT; Peroxisome proliferator-activated receptors; PPAR gamma - metabolism; PPAR-γ; Proteins; Rats; Rats, Wistar; Renal function; Side effects; Signal Transduction - drug effects; Urea - blood; Uric Acid - blood
• ISSN: 0024-3205; 1879-0631
• DOI: 10.1016/j.lfs.2021.119349

Gentamicin (GM) is an aminoglycoside antibiotic effectively used for severe/life-threatening infections. However, the clinical application of GM is limited by nephrotoxic side effects. Diosmin (DS) is a flavonoid with a wide range of bioactivities. However, its therapeutic potential in GM-induced nephrotoxicity remains unclear. Rats received GM (100 mg/kg, i.p.) for 7 days either separately or in combination with oral DS (50 mg/kg). GM injection disrupted kidney function along with oxidant/antioxidant imbalance. Also, GM significantly decreased renal nuclear factor erythroid 2-related factor 2 (Nrf2), glutamyl cysteine synthetase (GCLC), heme oxygenase-1 (HO-1), superoxide dismutase3 (SOD-3), protein kinase B (AKT), and p-AKT expressions along with Kelch-like ECH-associated protein 1 (KEAP1) up-regulation. On the contrary, DS administration significantly attenuated GM-induced kidney dysfunction and restored kidney oxidant/antioxidant status. In addition, co-treatment with DS plus GM significantly enhanced Nrf2, GCLC, HO-1, SOD3, AKT, and p-AKT expressions along with KEAP1 down-regulation. Additionally, GM-treated rats exhibited a significant decrease in the expressions of renal peroxisome-proliferator activated receptor-gamma (PPAR-γ) and this reduction was alleviated by DS treatment. Furthermore, histopathological findings demonstrated that DS significantly reduced the GM-induced histological abrasions. Besides, an in-silico study was conducted to confirm our biochemical results. Interestingly, in-silico results strongly supported our biochemical investigation by studying the binding affinity of DS to KEAP1, AKT, and PPAR-γ proteins. DS could be a promising protective agent against GM-induced nephrotoxicity through targeting of KEAP1/Nrf2/ARE, AKT, and PPAR-γ signaling pathways. •GM mediated oxidative stress injury in the kidney.•DS restored kidney function and oxidant/antioxidant balance.•DS modulated KEAP1/Nrf2/ARE, AKT, and PPAR-γ signaling pathways.•In silico study validates AKT, KEAP1, and PPAR-γ as potential targets for DS therapy.