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 sc) supplementation plus castration (CTX) in the male Sprague-Dawley rat starting at 13-15 mo of age, equivalent to a late 30- to 40-yr-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-h creatinine excretion, plasma creatinine, and creatinine clearance did not differ in E2 + CTX compared with Control by 22-24 mo of age, or following 9 mo of FHT. Lean mass was significantly reduced in E2 + CTX vs. 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 vs. Control, suggesting decreased renal filtration. Proteinuria, urinary kidney injury molecule-1 (KIM-1; a marker of proximal tubule injury), and glomerular injury score were significantly reduced in E2 + CTX vs. 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.NEW & NOTEWORTHY Whether enhanced renal risk is associated with chronic estrogen supplementation in the aging male is unknown. Using an experimental model of feminizing hormone therapy (FHT), 17β-estradiol (E2) plus castration (CTX) in male rats initiated after 1 yr of age, renal injury was not increased compared with age-matched male Controls. Whether renal function was impaired remains unclear, highlighting the need to establish more accurate methods to assess the biological effects of FHT on renal function.