Metcalfe Peter D, Leslie Jeffrey A, Campbell Matthew T, Meldrum Daniel R, Hile Karen L, Meldrum Kirstan K
Departments of Urology and Surgery, Indiana University School of Medicine, Indianapolis, IN 46202, USA.
Am J Physiol Endocrinol Metab. 2008 Feb;294(2):E435-43. doi: 10.1152/ajpendo.00704.2006. Epub 2007 Dec 11.
Upper urinary tract obstruction is a common cause of renal dysfunction in children and adults. While there is clinical evidence of an increased male incidence and mortality rate with acute renal failure, the effect of gender and testosterone on obstructive renal injury has not previously been evaluated. We hypothesized that testosterone exacerbates proinflammatory TNF-alpha production and proapoptotic and profibrotic signaling during renal obstruction, resulting in increased apoptotic cell death and tubulointerstitial fibrosis. To study this, male, female, castrated male, and testosterone-treated oophorectomized female rats were subjected to sham operation or 3 days of unilateral ureteral obstruction (UUO). Renal cortical tissue was then analyzed for TNF-alpha production; proapoptotic caspase-8, -9, and -3 activity; apoptotic cell death; profibrotic transforming growth factor-beta1 production; and alpha-smooth muscle actin expression. In a separate arm, glomerular filtration rate (inulin clearance) was measured in rats pre- and post-UUO. Male and testosterone-treated oophorectomized female rats demonstrated a significant increase in TNF-alpha production, caspase activity, apoptotic cell death, tubulointerstitial fibrosis, and renal dysfunction during UUO compared with castrated males and normal female rats subjected to the same time course of obstruction. These results demonstrate that endogenous testosterone production in normal male rats and testosterone exogenously administered to oophorectomized females significantly increases TNF production and proapoptotic and profibrotic signaling during renal obstruction, resulting in increased apoptotic cell death, tubulointerstitial fibrosis, and renal dysfunction.
上尿路梗阻是儿童和成人肾功能不全的常见原因。虽然有临床证据表明急性肾衰竭的男性发病率和死亡率有所增加，但性别和睾酮对梗阻性肾损伤的影响此前尚未得到评估。我们推测，睾酮会在肾梗阻期间加剧促炎细胞因子肿瘤坏死因子-α（TNF-α）的产生以及促凋亡和促纤维化信号传导，从而导致凋亡性细胞死亡增加和肾小管间质纤维化。为了研究这一点，对雄性、雌性、去势雄性和接受睾酮治疗的卵巢切除雌性大鼠进行假手术或3天的单侧输尿管梗阻（UUO）。然后分析肾皮质组织中TNF-α的产生、促凋亡的半胱天冬酶-8、-9和-3的活性、凋亡性细胞死亡、促纤维化的转化生长因子-β1的产生以及α-平滑肌肌动蛋白的表达。在另一个实验中，测量了大鼠UUO前后的肾小球滤过率（菊粉清除率）。与接受相同梗阻时间的去势雄性大鼠和正常雌性大鼠相比，雄性大鼠和接受睾酮治疗的卵巢切除雌性大鼠在UUO期间TNF-α的产生、半胱天冬酶活性、凋亡性细胞死亡、肾小管间质纤维化和肾功能不全均显著增加。这些结果表明，正常雄性大鼠内源性产生的睾酮以及外源性给予卵巢切除雌性大鼠的睾酮，在肾梗阻期间会显著增加TNF的产生以及促凋亡和促纤维化信号传导，从而导致凋亡性细胞死亡增加、肾小管间质纤维化和肾功能不全。
