Chronic estrogen supplementation in the aging castrated male rat is not associated with renal injury or activation of the renin angiotensin system

The biological effects of chronic estrogen supplementation on renal function and injury with aging in men are unknown. Using an experimental model of feminizing hormone therapy (FHT) induced by 17β-estradiol (E2) (5 mg/kg, s.c.) supplementation plus castration (CTX) in the male Sprague Dawley rat starting at 13-15 months of age, equivalent to a late thirty- to forty-year-old man, we tested the hypothesis that FHT is associated with impaired renal function and renal injury with aging associated with activation of the renin angiotensin system (RAS). However, 24-hour creatinine excretion, plasma creatinine, and creatinine clearance did not differ in E2+CTX compared to Control by 22-24 months of age, or following 9 months of FHT. Lean mass was significantly reduced in E2+CTX versus Control, but creatinine clearance adjusted to lean mass did not differ. Serum cystatin C, a more reliable biomarker for renal function, was unchanged; urinary cystatin C was reduced, suggesting no renal impairment. However, cystatin C clearance was reduced in E2+CTX versus Control, suggesting decreased renal filtration. Proteinuria, urinary KIM-1 (a marker of proximal tubule injury), and glomerular injury score were significantly reduced in E2+CTX versus Control; however, albuminuria did not differ. Renal angiotensinogen mRNA expression was significantly decreased in E2+CTX, whereas urinary angiotensinogen, renal renin, and renal angiotensin type 1 receptor mRNA expression did not differ. Collectively, these results suggest that the biological effects of FHT in the aging male are not associated with increased renal injury or inappropriate activation of the RAS; whether renal function is altered remains unclear.