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

## TL;DR

This study finds that psychological stress worsens kidney damage from chemotherapy in rats, with female rats being more vulnerable.

## Contribution

The study reveals sex-specific effects of social stress on cisplatin-induced renal oxidative stress and apoptosis in rats.

## Key findings

- Social stress increased renal oxidative damage in both male and female rats despite mannitol protection.
- Female rats showed increased apoptosis markers, indicating greater vulnerability to stress and cisplatin.
- Mannitol failed to fully protect against stress-induced kidney damage in the study.

## Abstract

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.

Cancer treatment extends beyond treatment itself, as psychological stress exposure occurs after treatment outcomes.This study investigates social‐Single Prolonged Stress (social‐SPS) impacts on kidney oxidative stress in male and female Wistar rats exposed to cisplatin.Additionally, it delves into the divergent apoptotic patterns observed in both sexes.Our findings indicate that social‐SPS exacerbates the toxic side effects of cisplatin, with female rats displaying heightened susceptibility to stress compared to males under this protocol.The study reveals no significant changes in hepatorenal biomarkers and oxidative stress in the liver.Our study highlights the potential of stress modulation to influence cisplatin toxicity, which may have implications for personalized cancer treatment approaches.

Cancer treatment extends beyond treatment itself, as psychological stress exposure occurs after treatment outcomes.

This study investigates social‐Single Prolonged Stress (social‐SPS) impacts on kidney oxidative stress in male and female Wistar rats exposed to cisplatin.

Additionally, it delves into the divergent apoptotic patterns observed in both sexes.

Our findings indicate that social‐SPS exacerbates the toxic side effects of cisplatin, with female rats displaying heightened susceptibility to stress compared to males under this protocol.

The study reveals no significant changes in hepatorenal biomarkers and oxidative stress in the liver.

Our study highlights the potential of stress modulation to influence cisplatin toxicity, which may have implications for personalized cancer treatment approaches.