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首页> 外文期刊>American Journal of Physiology >Testosterone exacerbates obstructive renal injury by stimulating TNF-alpha production and increasing proapoptotic and profibrotic signaling
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Testosterone exacerbates obstructive renal injury by stimulating TNF-alpha production and increasing proapoptotic and profibrotic signaling

机译：睾丸激素通过刺激TNF-α的产生并增加促凋亡和促纤维化信号传导而加剧阻塞性肾损伤

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First published December 11, 2007; doi:10.1152/ajpendo.00704.2006.-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 tubulointer-stitial 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 1 production; and alpha-smooth muscle actin expression. In aseparate 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.
机译：首次发布于2007年12月11日; doi：10.1152 / ajpendo.00704.2006.-上尿路梗阻是儿童和成人肾功能不全的常见原因。尽管有临床证据表明，急性肾功能衰竭会增加男性发病率和死亡率，但之前尚未评估性别和睾丸激素对阻塞性肾损伤的影响。我们假设睾丸激素会加剧肾梗阻期间促炎性TNF-α的产生以及促凋亡和促纤维化的信号传导，从而导致凋亡细胞死亡和肾小管间质纤维化增加。为了对此进行研究，对雄性，雌性，去势雄性和经睾丸激素处理的雌性大鼠进行假手术或三天的单侧输尿管阻塞（UUO）。然后分析肾皮质组织的TNF-α产生;凋亡的半胱天冬酶8，-9和-3活性;凋亡细胞死亡;纤维变性转化生长因子1的产生;和α-平滑肌肌动蛋白的表达。在单独的手臂中，在UUO之前和之后测量大鼠的肾小球滤过率（菊粉清除率）。与cast割的雄性和正常雌性大鼠在相同时间阻塞时相比，UUO期间雄性和睾丸激素治疗的经卵巢切除的雌性大鼠表现出TNF-α产生，胱天蛋白酶活性，凋亡细胞死亡，肾小管间质纤维化和肾功能障碍的显着增加。这些结果表明，正常雄性大鼠的内源性睾丸激素的生产以及经去卵巢切除的雌性大鼠外源性给予的睾丸激素会显着增加肾脏梗阻期间的TNF生成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，肾小管间质纤维化和肾功能障碍。

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