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The Presence of Testis Determines Aristolochic Acid-Induced Nephrotoxicity in Mice
Wei-Long Li1, Babu J Padanilam2, Jinu Kim1,3
1Interdisciplinary Graduate Program in Advanced Convergence Technology & Science, Jeju National University, Jeju 63243, Republic of Korea.
Abstract:
Aristolochic acid (AA) is notorious for inducing nephrotoxicity, but the influence of sex on AA-induced kidney injury was not clear. This study sought to investigate sex differences in kidney dysfunction and tubular injury induced by AA. Male and female mice were bilaterally orchiectomized and ovariectomized, respectively. Fourteen days after gonadectomy, the mice were intraperitoneally injected with AA (10 mg/kg body weight/day) daily for 2 days and sacrificed 7 days after the first injection. Body weight, kidney function, and tubular structure were assessed. When compared between male and female non-gonadectomized mice, AA-induced body weight loss was greater in male mice than in female mice. Functional and structural damages in male kidneys were markedly induced by AA injection, but kidneys in AA-injected female mice showed no or mild damages. Ovariectomy had no effect on AA-induced nephrotoxic acute kidney injury in female mice. However, orchiectomy significantly reduced body weight loss, kidney dysfunction, and tubular injury in AA-induced nephrotoxicity in male mice. This study has demonstrated that testis causes AA-induced nephrotoxic acute kidney injury.
Insights
Aristolochic acid causes kidney injury, with males being more susceptible. Testis removal protected male mice from this aristolochic acid-induced nephrotoxicity, indicating a protective role of the testis.
Area of Science:
- Toxicology
- Nephrology
- Endocrinology
Background:
- Aristolochic acid (AA) is a known nephrotoxin.
- The role of sex in AA-induced kidney injury remains unclear.
- Understanding sex differences is crucial for predicting and managing AA toxicity.
Purpose of the Study:
- To investigate sex-based differences in aristolochic acid-induced kidney dysfunction and tubular injury.
- To determine the influence of gonads (testis and ovary) on AA nephrotoxicity.
Main Methods:
- Male and female mice underwent gonadectomy (orchiectomy and ovariectomy, respectively).
- Mice were injected with aristolochic acid (10 mg/kg/day for 2 days).
- Kidney function, body weight, and tubular structure were assessed 7 days post-injection.
Main Results:
- AA induced greater body weight loss and more severe kidney damage in male mice compared to females.
- Ovariectomy did not alter AA-induced nephrotoxicity in females.
- Orchiectomy significantly attenuated body weight loss, kidney dysfunction, and tubular injury in AA-treated males.
Conclusions:
- The testis plays a significant role in mediating aristolochic acid-induced nephrotoxic acute kidney injury in males.
- Males are more vulnerable to AA nephrotoxicity than females, a difference influenced by the presence of testes.
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