Dose-dependent effects of dihydrotestosterone in the streptozotocin-induced diabetic rat kidney.
We recently reported that castration exacerbates albuminuria, glomerulosclerosis, and tubulointerstitial fibrosis associated with diabetic renal disease. The aim of the present study was to examine whether these effects of castration can be attenuated with dihydrotestosterone (DHT) supplementation. The study was performed in castrated male Sprague-Dawley, streptozotocin-induced diabetic rats treated with 0 mg/day DHT (DHT(0)), 0.75 mg/day DHT (DHT(0.75)), or 2.0 mg/day DHT (DHT(2.0)) for 14 wk. Treatment with 0.75 mg/day DHT attenuated castration-associated increases in urine albumin excretion (DHT(0), 81.2 +/- 18.1; DHT(0.75), 26.57 +/- 5.8 mg/day; P < 0.05), glomerulosclerosis (DHT(0), 1.1 +/- 0.79; DHT(0.75), 0.43 +/- 0.043 arbitrary units; P < 0.001), tubulointerstitial fibrosis (DHT(0), 1.3 +/- 0.12; DHT(0.75), 1.1 +/- 0.096 AU; P < 0.05), collagen type IV [DHT(0), 3.2 +/- 0.11; DHT(0.75), 2.1 +/- 0.070 relative optical density (ROD); P < 0.01], transforming growth factor-beta (DHT(0), 3.2 +/- 0.16; DHT(0.75), 2.1 +/- 0.060 ROD; P < 0.01), IL-6 (DHT(0), 0.37 +/- 0.011; DHT(0.75), 0.27 +/- 0.014 ROD; P < 0.05), and protein expression and reduced CD68-positive cell abundance (DHT(0), 17 +/- 0.86; DHT(0.75), 4.4 +/- 0.55 cells/mm(2); 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, whereas 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.
Xu
Qin
Q
Department of Medicine, Georgetown University Medical Center, Washington, District of Columbia, USA.
Prabhu
Anjali
A
Xu
Shujing
S
Manigrasso
Michaele B
MB
Maric
Christine
C
D000419:Albuminuria / Q000517:prevention & control; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism; D015214:Antigens, Differentiation, Myelomonocytic / Q000378:metabolism; D017209:Apoptosis / Q000187:drug effects; D001786:Blood Glucose / Q000187:drug effects; D001794:Blood Pressure / Q000187:drug effects; D024141:Collagen Type IV / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D003928:Diabetic Nephropathies / Q000209:etiology / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control*; D013196:Dihydrotestosterone / Q000008:administration & dosage* / Q000097:blood / Q000633:toxicity; D004305:Dose-Response Relationship, Drug; D004343:Drug Implants; D004958:Estradiol / Q000097:blood; D005355:Fibrosis; D018836:Inflammation Mediators / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D007668:Kidney / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D008297:Male; D009919:Orchiectomy; D050199:Podocytes / Q000187:drug effects; D051381:Rats; D017207:Rats, Sprague-Dawley; D013739:Testosterone / Q000097:blood; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D000097382:CD68 Molecule
D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D001786:Blood Glucose; D024141:Collagen Type IV; D013196:Dihydrotestosterone; D004343:Drug Implants; D004958:Estradiol; D018836:Inflammation Mediators; D015850:Interleukin-6; D013739:Testosterone; D016212:Transforming Growth Factor beta; D014409:Tumor Necrosis Factor-alpha; C539355:CD68 protein, rat; D000097382:CD68 Molecule