Inhibition of estradiol synthesis attenuates renal injury in male streptozotocin-induced diabetic rats

Abstract

We previously showed that the male streptozotocin (STZ)-induced diabetic rat exhibits decreased circulating testosterone and increased estradiol levels. While supplementation with dihydrotestosterone is partially renoprotective, the aim of the present study was to examine whether inhibition of estradiol synthesis, by blocking the aromatization of testosterone to estradiol using an aromatase inhibitor, can also prevent diabetes-associated renal injury. The study was performed on male Sprague-Dawley nondiabetic, STZ-induced diabetic, and STZ-induced diabetic rats treated with 0.15 mg/kg of anastrozole, an aromatase inhibitor (Da) for 12 wk. Treatment with anastrozole reduced diabetes-associated increases in plasma estradiol by 39% and increased plasma testosterone levels by 187%. Anastrozole treatment also attenuated urine albumin excretion by 42%, glomerulosclerosis by 30%, tubulointerstitial fibrosis by 32%, along with a decrease in the density of renal cortical CD68-positive cells by 50%, and protein expression of transforming growth factor-β by 20%, collagen type IV by 29%, tumor necrosis factor-α by 28%, and interleukin-6 by 25%. Anastrozole also increased podocin protein expression by 18%. We conclude that blocking estradiol synthesis in male STZ-induced diabetic rats is renoprotective.

Characterization of the development of renal injury in Type-1 diabetic Dahl salt-sensitive rats

“…These data suggest that the initial changes in renal hemodynamics during the early phase of diabetes are due to adaptive renal hypertrophy, which is later followed by an increase in GFR (hyperfiltration), leading to the development of renal injury and chronic kidney disease. STZ has been extensively used to induce diabetes in many strains of rats, including SD (1,20,21,25), Wistar-Kyoto (WKY) (6,32), and spontaneously hypertensive (SHR) strains (6, 7, 10 -12, 16). Previous studies have demonstrated that the development of renal injury is greater in STZ-treated SHR rats compared with WKY rats.…”

Renoprotective Effect of Pioglitazone by the Prevention of Glomerular Hyperfiltration through the Possible Restoration of Altered Macula Densa Signaling in Rats with Type 2 Diabetic Nephropathy

“…The sections were washed three times in Tris-buffered saline (pH 7.4) containing 0.1% Tween 20 for 5 min and treated with primary antibody which is rabbit anti-transforming growth factor β1 antibody (No. sc-146, TGF-β1; Santa Cruz Biotechnology Inc., Santa Cruz, Calif., USA) [21] diluted 1:200, rabbit anti-cyclooxygenase (COX)-2 antibody (No. 160126; Cyman Chemical Company, Ann Arbor, Mich., USA) [22] diluted 1:1,000, rabbit anti-neuronal NO synthase (nNOS) antibody (No.…”

RAS and sex differences in diabetic nephropathy

“…Interestingly, while diabetic male rats previously presented a reduction in the ratio of AR to ER protein expression in the renal cortex compared with nondiabetic animals (67,96), the dual treatment with DHT and anastrozole restored this ratio (66). Considering that changes in sex hormone receptor expression in the diabetic kidney may reflect altered levels of circulating androgens and estrogens, it is conceivable that the diminished renal alterations observed after this dual treatment were achieved by restoring relative balance between sex hormones.…”