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Testosterone contributes sex differences of urinary biomarkers for nephrotoxicity in rats

Satoshi Tsuji1, Aya Hasegawa-Izaki1, Bunichiro Ogawa1

  • 1Drug Safety and Pharmacokinetics, Taisho Pharmaceutical Co., Ltd.

The Journal of Toxicological Sciences
|August 3, 2025
PubMed

Insights

Testosterone influences sex differences in kidney function biomarkers. This study found testosterone affects urinary biomarker excretion and renal megalin levels in rats, suggesting a key role in sex-based nephrotoxicity.

Area of Science:

  • Toxicology
  • Nephrology
  • Endocrinology

Background:

  • Urinary biomarkers are crucial for assessing drug-induced kidney injury in non-clinical studies.
  • Existing research on nephrotoxicity lacks comprehensive understanding of sex-based differences in biomarker excretion.
  • Previous work indicated sex differences in urinary biomarker excretion linked to endogenous testosterone levels.

Purpose of the Study:

  • To investigate the impact of testosterone on sex differences in urinary biomarker excretion and renal cortical protein levels.
  • To determine how blood testosterone levels contribute to observed sex-based variations in kidney function markers.
  • To explore the role of testosterone in regulating renal protein expression related to kidney function.

Main Methods:

  • Subcutaneous administration of testosterone to female rats over 4 weeks.
  • Comparison of urinary biomarker and renal cortical protein levels between testosterone-treated female rats and control male rats.
  • Quantification of specific urinary biomarkers including LAP, γ-GTP, Cys-C, L-FABP, β2MG, and Kim-1.
  • Assessment of megalin protein levels in the renal cortex.

Main Results:

  • Testosterone treatment increased urinary excretion of LAP, γ-GTP, Cys-C, L-FABP, and β2MG in female rats.
  • Urinary excretion of Kim-1 decreased following testosterone administration.
  • Renal cortical megalin protein levels were higher in female rats than male rats.
  • Testosterone treatment decreased megalin levels in the renal cortex of female rats.

Conclusions:

  • Blood testosterone levels play a significant role in mediating sex differences in the urinary excretion of low-molecular-weight proteins.
  • Testosterone regulates the expression of megalin in the renal cortex, impacting biomarker handling.
  • Findings suggest testosterone is a key factor in sex-specific nephrotoxicity assessment.
Keywords:
RatsSex differenceTestosteroneUrinary biomarker

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