Influence of Orchiectomy on Sex-Specific Responses to Aristolochic Acid-Induced Renal Injury

Aristolochic acid (AA) is widely recognized for its nephrotoxic effects; however, the role of sex in AA-induced renal injury remains ambiguous. The present investigation aimed to elucidate the sex-based disparities in renal dysfunction and tubular damage resulting from AA exposure. Male and female murine models underwent bilateral orchiectomy and ovariectomy, respectively. Fourteen days post-gonadectomy, the subjects were administered AA (10 mg/kg body weight/day) via intraperitoneal injection for two consecutive days, followed by euthanasia seven days subsequent to the initial injection. Parameters such as body weight, renal functionality, and tubular morphology were meticulously evaluated. A comparative analysis between male and female non-gonadectomized subjects revealed that the weight reduction induced by AA was significantly more pronounced in male mice (H = 20.041, dF = 3, P
0.001, as determined by the Kruskal-Wallis test). Additionally, functional and structural impairments in male kidneys were significantly exacerbated following AA administration, whereas the kidneys of AA-treated female mice exhibited either negligible or mild injuries (F = 83.618, P < 0.001 on plasma creatinine level; F = 3971.979, P < 0.001 on tubular injury score in the cortex, as determined by the analysis of variance). Ovariectomy did not influence AA-induced nephrotoxic acute kidney injury in the female cohort (F = 0.0955, P = 0.760 on body weight change; F = 0.211, P = 0.651 on plasma creatinine level; F = 2.985, P = 0.099 on tubular injury score in the cortex, as determined by the analysis of variance). In contrast, orchiectomy resulted in a significant attenuation of weight loss, renal dysfunction, and tubular damage in the context of AA-induced nephrotoxicity among male mice (F = 8.541, P = 0.008 on body weight change; F = 8.892, P = 0.007 on plasma creatinine level, as determined by the analysis of variance; H = 19.767, dF = 3, P
0.001 on tubular injury score in the cortex, as determined by the Kruskal-Wallis test). This research has conclusively established that the presence of testes contributes to the development of AA-induced nephrotoxic acute kidney injury. Future studies should investigate the molecular mechanisms by which gonadal hormones, such as androgens and estrogens, modulate AA-induced nephrotoxicity. Additionally, researchers should explore sex-specific therapeutic strategies, which may pave the way for translating these findings into clinical trials.