Modulation of the Keap1/Nrf2/HO-1 signaling axis by ferulic acid and hesperidin in the mitigation of cyclophosphamide-induced nephrotoxicity: In vivo and in silico approaches.

BACKGROUND

Although cyclophosphamide (CYP) is still a mainstay of cancer chemotherapy; yet, its clinical utility is often undermined by nephrotoxicity.

AIM OF THE STUDY: This study aimed to assess the potential protective effects of ferulic acid (FA) and hesperidin (HSP) against CYP-induced nephrotoxicity and the underlying mechanisms of such effects.

METHODS

Thirty-six rats were allocated into six groups. These were group I (control group), group II (FA group), group III (HSP group), group IV (CYP group) which received a single dose of CYP (150 mg/kg intraperitoneal injection on day 16), group V (CYP + FA group) which received FA (50 mg/kg orally for 15 days before CYP injection), and group VI (CYP+HSP) which received HSP (100 mg/kg orally for 15 days before CYP injection). We assessed renal function markers, oxidative stress markers, inflammatory cytokines, and Keap1, Nrf2, HO-1, PPARγ, and TNF-α expression, as well as histopathological and ultrastructural analyses.

RESULTS

CYP-induced nephrotoxicity was evidenced by the increase in serum urea, creatinine, and KIM-1 levels, decrease in albumin levels, as well as renal histopathological and ultrastructural abnormalities. CYP denoted a significant reduction in antioxidant markers; CAT, SOD, and TAC, an increase in the lipid peroxidation marker; MDA, and an upregulation of inflammatory cytokines; TNF-α, IL-1β, and IL-6. Moreover, CYP showed a significant upregulation of the expression of Keap1 and TNF-α, and significant downregulation of Nrf2, HO-1, and PPARγ expression. On the other hand, FA and HSP significantly ameliorated these CYP-induced abnormalities.

CONCLUSION

FA and HSP may have a promising protective effect against CYP-induced nephrotoxicity via targeting Keap1/Nrf2/HO-1 signaling pathway.