Could hesperetin ameliorate doxorubicin-induced nephrotoxicity in rats via its antioxidant, antiapoptotic, and anti-inflammatory properties?

Doxorubicin (DOX), from the anthracycline family, is a widely utilized chemotherapy for various malignancies; however, its utility is limited due to the serious adverse reactions, particularly on the kidneys, primarily related to oxidative stress, inflammation, and apoptosis. Hesperetin (HES), the citrus fruit derivative, is a naturally occurring flavonoid. Previous studies underscored HES's protective efficacy against renal damage in several disorders in rodents through its proven antioxidant, antiapoptotic, and anti-inflammatory properties. This work explored the protecting role of HES against the nephrotoxic effects of DOX and the possible underlying mechanisms. Nephrotoxicity was induced in rats via administering six equal doses of DOX (3 mg/kg/week, i.p) for six consecutive weeks. The treated group received HES (50 mg/kg/day, p.o.) simultaneously with DOX. Rats' body and kidney weights, serum creatinine, blood urea nitrogen (BUN), and albumin were estimated. Kidney tissue was treated to assess redox status, histopathological, and immunohistochemical alterations. Compared to the controls, coadministration of HES with DOX significantly reduced the serum BUN and creatinine, elevated the serum albumin, amended the glomerular distortion and tubular epithelial degeneration, decreased collagen deposition, vascular congestion, and inflammatory cells in addition to the significant attenuation of inflammatory cytokines and proapoptotic markers. Our study is the first of its kind to underscore the HES's antioxidant, antiapoptotic, and anti-inflammatory activities in an experimental model of DOX-induced nephrotoxicity with emphasis on TNF-α, IL-1β, and IL-6 signaling pathway, rendering it as an effective therapeutic supplement that could alleviate the nephrotoxic effect of DOX.