Submitted on March 8, 2009
Revised on May 11, 2009
Accepted on June 2, 2009
Dose-dependent effects of dihydrotestosterone in the streptozotocin-induced diabetic rat kidney
Qin Xu, Anjali Prabhu, Shujing Xu, Michaele B. Manigrasso, and Christine Maric1*
1 University of Mississippi Medical Center
* To whom correspondence should be addressed. E-mail: cmaric{at}physiology.umsmed.edu.
We have recently reported that castration exacerbates albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis associated with diabetic renal disease. The aim of the present study was to examine if these effects of castration can be attenuated with dihydrotestosterone (DHT) supplementation. The study was performed in castrated male Sprague-Dawley, streptozotocin (STZ)-induced diabetic rats treated with 0 mg/day DHT (DHT0), 0.75 mg/day DHT (DHT0.75) or 2.0 mg/day DHT (DHT2.0) for 14 weeks. Treatment with 0.75 mg/day DHT attenuated castration-associated increases in urine albumin excretion (DHT0, 81.2±18.1; DHT0.75, 26.57±5.8 mg/day; P<0.05), glomerulosclerosis (DHT0, 1.1±0.79; DHT0.75, 0.43±0.043 AU; P<0.001), tubulointerstitial fibrosis (DHT0, 1.3±0.12; DHT0.75, 1.1±0.096 AU; P<0.05), collagen type IV (DHT0, 3.2±0.11; DHT0.75, 2.1±0.070 ROD; P<0.01), transforming growth factor-beta (DHT0, 3.2±0.16; DHT0.75, 2.1±0.060 ROD; P<0.01) and IL-6 (DHT0, 0.37±0.011; DHT0.75, 0.27±0.014 ROD; P<0.05) protein expression and reduced CD68-positive cell abundance (DHT0, 17±0.86; DHT0.75, 4.4±0.55 cells/mm2; P<0.001). In contrast, treatment with 2.0 mg/day DHT exacerbated all these parameters. These data suggest that the detrimental effects of castration in the diabetic kidney can be attenuated with low doses of DHT, while high doses augment the adverse effects of castration, and these effects appear to be influenced by estradiol. We conclude that the effects of DHT are dose-dependent but caution should be taken when DHT supplementation is considered in the treatment of diabetic renal disease.
