Targeted Modulation of Mitochondrial Oxidative Stress Ameliorates 5-Fluorouracil-Induced Renal Injury in BALB/c Mice.

Abstract

Background: The present study reports the protective effect conferred by scavenging mitochondrial oxidative stress (mtOS) in 5-fluorouracil (5-FU)-induced renal injury. Methods: 5-FU renal toxicity model was created by administering 5-FU (12 mg/kg b.w. intraperitoneally [i.p.], for 4 days) to male BALB/c mice. The protective effect of mitochondria-targeted antioxidant (MTA), Mito-TEMPO coadministered at a dosage of 0.1 mg/kg b.w. i.p., was established in terms of levels/expressions of renal injury markers, histopathological alterations, oxidative DNA damage, proinflammatory markers, mtOS, mitochondrial dysfunction, and modulation of apoptotic proteins and apoptotic cell death. Results: A significant rise in the levels of serum urea, uric acid, and creatinine was noted after 5-FU administration to the animals. Immunohistochemical and ELISA findings demonstrated significant decrease in podocin and conversely a significant increase in neutrophil gelatinase-associated lipocalin (NGAL) expression after 5-FU challenge. The histopathological analysis further revealed Bowman's capsule dilation, glomerular condensation, and vacuolar degeneration. Mito-TEMPO treatment significantly lowered renal injury markers, reversed the expressions of podocin and NGAL to normal, and restored normal histoarchitecture of renal tissue. Mitochondrial reactive oxygen species (mtROS), mtLPO, activity of mitochondrial enzyme complexes, and mitochondrial antioxidant defense status were significantly improved in Mito-TEMPO protected group as compared to the 5-FU group. Further, significantly decreased expression of 8-OHdG, reduction in apoptotic cell death, and modulation of apoptotic proteins Bax, Bcl-2, and caspase-3 were noted in Mito-TEMPO protected group, indicating its protective effect against 5-FU-induced renal injury. Conclusion: The approach of targeting mtOS using MTA, Mito-TEMPO, may prove as safe adjuvant in alleviating renal toxicity during 5-FU chemotherapy.