Chrysin as a therapeutic adjunct to prevent isoniazid-induced nephrotoxicity in rats: Biochemical, molecular, and histopathological evidence

Isoniazid (INZ) is an effective antituberculosis drug; however, its use is associated with nephrotoxicity due to the induction of oxidative stress, inflammation, and apoptosis. This study investigated whether chrysin (CHR), a natural flavonoid with antioxidant and anti-inflammatory properties, could protect against INZ-induced nephrotoxicity in rats. Male Sprague Dawley rats were divided into five groups: Control, INZ, CHR, INZ+CHR25 and INZ+CHR50. Biochemical assays, ELISA, RT-qPCR, Western blot and immunohistochemistry were used to evaluate renal function markers, oxidative stress parameters, inflammatory mediators, survival genes, apoptosis, autophagy and endoplasmic reticulum (ER) stress-associated genes. INZ treatment was found to significantly increase serum urea and creatinine levels, cause glomerular and tubular damage, raise MDA levels, lower antioxidant enzymes (SOD, CAT and GPx) and GSH levels, and suppress Nrf-2, HO-1, SIRT1 and PGC1α. Furthermore, INZ treatment was found to upregulate inflammatory markers (NFκB, STAT3, TNF-α, IL-1β, MAPK and JNK), apoptotic markers (Bax, Bcl2, P53, and P62), components of the PI3K/AKT/mTOR pathway and ER stress/autophagy genes (GRP78, ATF6, PERK, IRE-1α, CHOP and Beclin-1). Co-administration of CHR reversed these alterations in a dose-dependent manner, enhancing antioxidant defenses, attenuating inflammation, apoptosis, autophagy, and ER stress. CHR also reduced kidney injury by increasing nephrin expression and decreasing KIM-1 expression immunohistochemically. These findings suggest that CHR has a nephroprotective effect against INZ-induced renal injury through multi-target molecular mechanisms and demonstrate its potential as an adjunctive therapy to reduce drug-induced nephrotoxicity.