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

• Published in: American journal of physiology. Regulatory, integrative and comparative physiology Vol. 304; no. 11; p. R951
• Main Authors: Soljancic, Andrea, Ruiz, Arnaldo Lopez, Chandrashekar, Kiran, Maranon, Rodrigo, Liu, Ruisheng, Reckelhoff, Jane F, Juncos, Luis A
• Format: Journal Article
• Language: English
• Published: United States 01-06-2013
• Subjects: Acute Kidney Injury - physiopathology; Acute Kidney Injury - prevention & control; 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; androgens; kidney injury molecule-1; vascular endothelial growth factor; sex
• ISSN: 1522-1490
• DOI: 10.1152/ajpregu.00360.2012

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.