Persistent Renal Oxidative Stress Despite Mannitol Nephroprotection: The Impact of <i>Social</i>‐Single Prolonged Stress in Male and Female Rats Exposed to Cisplatin

Cisplatin (CIS) is a chemotherapeutic agent known for nephrotoxicity through oxidative stress. Cancer treatment is also associated with psychological stress. Repeated exposure to social-single prolonged stress (social-SPS) modulates long-term renal oxidative damage and apoptosis in a sex-dependent manner in rats treated with cisplatin (CIS), despite mannitol's nephroprotective effects. We investigated whether repeated exposure to social-single prolonged stress (social-SPS) modulates long-term renal oxidative damage and apoptosis in male and female rats treated with CIS and mannitol. Male and female Wistar rats were divided into three groups: control, CIS + mannitol, and CIS + mannitol + social-SPS. Mannitol was administered 1 h before CIS (2 mg/kg/day, i.p., for 5 days). Social-SPS was applied at three time points. At postnatal day 68, blood and kidney samples were collected for biochemical and Western blot analyses. Plasma renal biomarkers remained unchanged across groups. However, social-SPS increased renal lipid peroxidation (TBARS) and protein oxidation (carbonyl content) in both sexes. CIS+social-SPS decreased catalase activity and altered SOD, GST, and NPSH in a sex-dependent manner. Only female rats showed increased renal BAX/Bcl2 ratio, indicating apoptosis. In males, Na⁺/K⁺-K-ATPase activity correlated positively with NPSH content. Despite mannitol nephroprotection, social stress exacerbated renal oxidative stress. Female rats were more susceptible to apoptosis, suggesting sex-specific vulnerability to combined CIS and stress exposure. These findings highlight the importance of considering psychological stress and sex as modulators of chemotherapeutic toxicity and may inform future strategies for personalized cancer care.