Department of Physiology and Biophysics, University of Mississippi Medical Center, 2500 North State St., Jackson, MS 39216, USA.
Am J Physiol Renal Physiol. 2012 May 1;302(9):F1203-9. doi: 10.1152/ajprenal.00569.2011. Epub 2012 Feb 1.
Our previous studies showed that streptozotocin (STZ)-induced diabetic male rats have increased estradiol and decreased testosterone levels that correlate with renal injury (Xu Q, Wells CC, Garman GH, Asico L, Escano CS, Maric C. Hypertension 51: 1218-1224, 2008). We further showed that either supplementing dihydrotestosterone (DHT) or inhibiting estradiol biosynthesis in these diabetic rats was only partially renoprotective (Manigrasso MB, Sawyer RT, Marbury DC, Flynn ER, Maric C. Am J Physiol Renal Physiol 301: F634-F640, 2011; Xu Q, Prabhu A, Xu S, Manigrassso MB, Maric C. Am J Physiol 297: F307-F315, 2009). The aim of this study was to test the hypothesis that the combined therapy of DHT supplementation and inhibition of estradiol synthesis would afford better renoprotection than either treatment alone. The study was performed in 12-wk-old male nondiabetic (ND), STZ-induced diabetic (D), and STZ-induced diabetic rats that received the combined therapy of 0.75 mg/day of DHT along with 0.15 mg · kg(-1) · day(-1) of an aromatase inhibitor, anastrozole (Dta), for 12 wk. Treatment with the combined therapy resulted in attenuation of albuminuria by 84%, glomerulosclerosis by 55%, and tubulointerstitial fibrosis by 62%. In addition, the combined treatment decreased the density of renal cortical CD68-positive cells by 70% and decreased protein expression of transforming growth factor-β protein expression by 60%, collagen type IV by 65%, TNF-α by 55%, and IL-6 by 60%. We conclude that the combined treatment of DHT and blocking aromatase activity in diabetic male STZ-induced diabetic rats provides superior treatment than either treatment alone in the prevention of diabetic renal disease.
我们之前的研究表明，链脲佐菌素（STZ）诱导的糖尿病雄性大鼠的雌二醇水平升高，睾丸酮水平降低，这与肾脏损伤有关（Xu Q、Wells CC、Garman GH、Asico L、Escano CS、Maric C. Hypertension 51: 1218-1224, 2008）。我们进一步表明，在这些糖尿病大鼠中补充二氢睾丸酮（DHT）或抑制雌二醇的生物合成只能部分保护肾脏（Manigrasso MB、Sawyer RT、Marbury DC、Flynn ER、Maric C. Am J Physiol Renal Physiol 301: F634-F640, 2011；Xu Q、Prabhu A、Xu S、Manigrassso MB、Maric C. Am J Physiol 297: F307-F315, 2009）。本研究的目的是验证这样一个假设，即 DHT 补充和雌二醇合成抑制的联合治疗比任何单一治疗都能提供更好的肾脏保护作用。该研究在 12 周龄的非糖尿病（ND）、STZ 诱导的糖尿病（D）和接受每天 0.75 毫克 DHT 联合 0.15 毫克/公斤/天芳香化酶抑制剂 anastrozole（Dta）治疗 12 周的 STZ 诱导的糖尿病大鼠中进行。联合治疗使白蛋白尿减少 84%，肾小球硬化减少 55%，肾小管间质纤维化减少 62%。此外，联合治疗使肾皮质 CD68 阳性细胞密度降低 70%，转化生长因子-β蛋白表达降低 60%，IV 型胶原降低 65%，TNF-α降低 55%，IL-6降低 60%。我们得出结论，在预防糖尿病肾病方面，DHT 与阻断糖尿病雄性 STZ 诱导的糖尿病大鼠的芳香酶活性联合治疗比任何单一治疗都提供更好的治疗效果。
