Protective role of testosterone in ischemia-reperfusion-induced acute kidney injury

Am J Physiol Regul Integr Comp Physiol. 2013 Jun 1;304(11):R951-8. doi: 10.1152/ajpregu.00360.2012. Epub 2013 Apr 3.


Men are at greater risk for renal injury and dysfunction after acute ischemia-reperfusion (I/R) than are women. Studies in animals suggest that the reason for the sex difference in renal injury and dysfunction after I/R is the protective effect of estrogens in females. However, a reduction in testosterone in men is thought to play an important role in mediating cardiovascular and renal disease, in general. In the present study, we tested the hypothesis that I/R of the kidney reduces serum testosterone, and that contributes to renal dysfunction and injury. Male rats that were subjected to renal ischemia of 40 min followed by reperfusion had a 90% reduction in serum testosterone by 3 h after reperfusion that remained at 24 h. Acute infusion of testosterone 3 h after reperfusion attenuated the increase in plasma creatinine and urinary kidney injury molecule-1 (KIM-1) at 24 h, prevented the reduction in outer medullary blood flow, and attenuated the increase in intrarenal TNF-α and the decrease in intrarenal VEGF at 48 h. Castration of males caused greater increases in plasma creatinine and KIM-1 at 24 h than in intact males with renal I/R, and treatment with anastrozole, an aromatase inhibitor, plus testosterone almost normalized plasma creatinine and KIM-1 in rats with renal I/R. These data show that renal I/R is associated with sustained reductions in testosterone, that testosterone repletion protects the kidney, whereas castration promotes renal dysfunction and injury, and that the testosterone-mediated protection is not conferred by conversion to estradiol.

Keywords: androgens; kidney injury molecule-1; sex; vascular endothelial growth factor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acute Kidney Injury / physiopathology
  • Acute Kidney Injury / prevention & control*
  • Anastrozole
  • Animals
  • Aromatase Inhibitors / pharmacology
  • Cell Adhesion Molecules / urine
  • Creatinine / blood
  • Male
  • Nitriles / pharmacology
  • Orchiectomy
  • Proteinuria / blood
  • Rats
  • Rats, Sprague-Dawley
  • Renal Circulation / physiology
  • Reperfusion Injury / physiopathology
  • Reperfusion Injury / prevention & control*
  • Testosterone / blood
  • Testosterone / pharmacology*
  • Testosterone / therapeutic use
  • Triazoles / pharmacology
  • Tumor Necrosis Factor-alpha / metabolism
  • Vascular Endothelial Growth Factor A / metabolism


  • Aromatase Inhibitors
  • Cell Adhesion Molecules
  • Havcr1protein, rat
  • Nitriles
  • Triazoles
  • Tumor Necrosis Factor-alpha
  • Vascular Endothelial Growth Factor A
  • Anastrozole
  • Testosterone
  • Creatinine