UROXIL attenuates cyclophosphamide-induced nephrotoxicity in rats by suppressing oxidative stress, endoplasmic reticulum stress, inflammation, and mitochondrial apoptosis.

Cyclophosphamide (CYP) is a widely used alkylating chemotherapeutic agent whose clinical utility is limited by dose-dependent nephrotoxicity. The efficacy of UROXIL in CYP-induced nephrotoxicity was investigated in this study. The groups: control, UROXIL, CYP, and UROXIL + CYP. Nephrotoxicity was induced by CYP administration, while UROXIL was applied prophylactically. Renal oxidative stress, antioxidant defense systems, histopathological alterations, endoplasmic reticulum (ER) stress, inflammatory signaling, and apoptotic pathways were evaluated using biochemical assays, histopathology, immunohistochemistry, immunofluorescence, RT-PCR, and Western blot analyses. CYP administration significantly increased malondialdehyde levels and suppressed glutathione content as well as superoxide dismutase (SOD) and glutathione (GSH) activities, indicating severe oxidative stress. CYP also induced marked tubular degeneration, necrosis, hemorrhage, and hyaline cast formation in renal tissues. Mechanistically, CYP activated ER stress signaling pathways, as evidenced by increased GRP78, PERK, IRE1, eIF2α, ATF4, and CHOP expression, and promoted inflammation through increased expression of NF-κB-gene related markers of the TLR4/NF-κB pathway. CYP increased cytochrome c, BAX, p38 MAPK and caspase 3 release and decreased Bcl-2 expression. UROXIL treatment significantly attenuated these molecular and histopathological alterations. In conclusion, UROXIL attenuates cyclophosphamide-induced renal injury by reducing oxidative stress, ER stress-associated alterations, inflammatory signaling, and apoptosis-related markers, suggesting its potential as a supportive agent against chemotherapy-associated renal toxicity.