Melatonin alleviates gentamicin-induced acute kidney injury through the Keap1/Nrf2/HO-1 signaling pathway

Area of Science:

• Nephrology
• Pharmacology
• Biochemistry

Background:

• Drug-induced nephrotoxicity is a significant clinical concern.
• Gentamicin (GM) is a vital antibiotic but frequently causes acute kidney injury (AKI).
• Melatonin, a natural antioxidant, shows potential in mitigating drug-induced kidney damage.

Purpose of the Study:

• To investigate the dose-dependent effects of GM on kidney function and injury.
• To elucidate the mechanisms underlying GM-induced nephrotoxicity.
• To evaluate the renoprotective effects and mechanisms of melatonin against GM-induced AKI.

Main Methods:

• Administered varying doses of GM to rats to assess dose-dependent nephrotoxicity.
• Measured urinary and serum biomarkers of kidney injury and dysfunction (KIM-1, NGAL, BUN, SCr).
• Performed histopathological analysis to evaluate renal tissue damage.
• Assessed oxidative stress markers (SOD, GSH, MDA) and the KEAP1/NRF2 pathway components (Keap1, NRF2, GPX1, NQO1, HO-1).
• Treated rats with melatonin to evaluate its protective effects.

Main Results:

• GM induced dose-dependent nephrotoxicity, significantly increasing kidney injury biomarkers (KIM-1, NGAL) and renal dysfunction markers (BUN, SCr) at doses ≥50 mg/kg.
• Histopathology showed progressive renal damage, including tubular injury and inflammation, with increasing GM doses.
• GM elevated oxidative stress by depleting SOD and GSH while increasing MDA.
• GM downregulated the KEAP1/NRF2 pathway, suppressing antioxidant gene expression.
• Melatonin treatment significantly ameliorated GM-induced AKI, normalizing biomarkers, reducing histopathological damage, restoring antioxidant capacity, and reactivating the KEAP1/NRF2 pathway.

Conclusions:

• GM causes dose-dependent nephrotoxicity and AKI through oxidative stress and KEAP1/NRF2 pathway dysregulation.
• Melatonin demonstrates significant renoprotective effects against GM-induced AKI.
• Melatonin's protective mechanism involves restoring antioxidant balance and reactivating the KEAP1/NRF2 pathway, highlighting its therapeutic potential.