The Effect of Exercise on Doxorubicin-Induced Nephrotoxicity in Male and Female Rats

Abstract

Doxorubicin (DOX) is a first-line chemotherapeutic agent used to treat a wide range of malignancies including breast and lymphatic cancers. However, the clinical use of DOX is limited due to off-target toxicity to healthy organs. DOX-induced nephrotoxicity is established in both cancer patients and experimental models, where it is hypothesized that oxidative damage to renal cells increases glomerular capillary permeability and tubular atrophy. In contrast, endurance exercise preconditioning has the potential to reduce renal edema and inflammation, improving glomerular filtration rate and urine creatinine clearance rate. Therefore, the purpose of this study was to investigate whether exercise preconditioning can protect against DOX-induced nephrotoxicity and elucidate differences between male and female rats. Young-adult male and female Sprague-Dawley rats were randomly separated into 4 groups: i) sedentary saline; ii) sedentary DOX (20 mg/kg IP); iii) exercise-trained saline; and iv) exercise-trained DOX. Exercise trained animals underwent 2 weeks of treadmill preconditioning for (5 days/wk, 60 min/day, 30 m/min @ 0% grade). Animals received saline or DOX 24hrs after the final exercise bout, followed by endpoint 48hrs post-treatment. Evaluation of inflammatory markers within the urine (i.e. IP10, AGP and NGAL) demonstrated elevated levels in DOX-treated males and females, regardless of exercise. Male rats receiving DOX had elevated levels of clusterin which was not found in female rodents suggesting a possible sex-difference. Moreover, urine creatinine levels were significantly increased following DOX treatment and reduced with exercise in males, with no significant differences in females. In summary, animals treated with doxorubicin had higher levels of markers for inflammation and renal disease, with minimal effects of exercise preconditioning to prevent these changes. Additionally, males demonstrated higher levels of renal toxicity suggesting that females may have a greater resistance to DOX-induced nephrotoxicity.R01 HL153140R01 HL144858 R01 HL144858 and R01 HL153140 This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.