ANGIOTENSIN IN RENAL RESPONSE TO URETERAL OBSTRUCTION

通过干扰肾脏的生长发育，先天性尿路 尿路梗阻是导致肾脏疾病的最重要原因之一。 婴儿和儿童的失败。梗阻性肾病也是一种 成人肾功能不全的重要原因。单边 输尿管梗阻(UUO)激活肾脏程序性细胞死亡 (细胞凋亡)和肾素-血管紧张素系统。这些反应更强烈 新生儿的时间比成人的长。血管紧张素II(Ang Ii)刺激转化生长因子-β1和肌成纤维细胞 转化，这可能导致间质纤维化的进展和 梗阻肾小管萎缩。然而，敏锐地追随UUO 外源性血管紧张素Ⅱ促进新生大鼠肾小管上皮细胞增殖 减少梗阻肾组织中的细胞凋亡。我们假设 肾脏血管紧张素II的生成增加是一种早期保护性反应 UUO，但继续生产Ang Il是不适应的。在 提出的研究计划中，肾素-血管紧张素系统将选择性地 抑制(依那普利、氯沙坦或PD123319)或刺激(Ang II) 新生鼠和成年UUO组和假手术组。肾间质 血管紧张素转换酶II的测定采用微透析法，单次给药反应 肾单位梗阻将通过显微穿刺术确定。此外, 具有1-4个血管紧张素原基因拷贝的转基因小鼠将被 受到UUO或假手术的影响。肾小管细胞破裂 (由局部接触者分布决定)和细胞凋亡(由 流式细胞术和TUNEL)及其调节剂(转化生长 因子-β1、聚集素和bc1-2)将通过mRNA分析进行检测 免疫组织化学方法检测蛋白质分布。肾间质 肌成纤维细胞转化和间质纤维化也将 下定决心。这些研究将阐明 肾素-血管紧张素系统调节肾细胞对UUO的反应， 并可能导致新的干预措施以避免肾脏疾病的进展 梗阻性肾病患者的肾功能不全。

By interfering with renal growth and development , congenital urinary tract obstruction constitutes one of the most important causes of renal failure in infants and children. Obstructive nephropathy is also a significant cause of renal insufficiency in the adult. Unilateral ureteral obstruction (UUO) activates renal programmed cell death (apoptosis) and the renin-angiotensin system. These responses are greater and more prolonged in the neonate than in the adult. Angiotensin II (ANG II) stimulates transforming growth factor-beta 1 and myofibroblast transformation, which may lead to progression of interstitial fibrosis and tubular atrophy in the obstructed kidney. However, acutely following UUO in the neonatal rat, exogenous ANG II increases tubular cell proliferation and decreases apoptosis in the obstructed kidney. We hypothesize that increased renal generation of ANG II is an early protective response to UUO, but that continued production of ANG Il is maladaptive. In the proposed research plan, the renin-angiotensin system will be selectively inhibited (by enalapril, losartan, or PD123319) or stimulated (by ANG II) in neonatal and adult rats with UUO or sham operation. Renal interstitial ANG II will be measured by microdialysis, and the response to single nephron obstruction will be determined by micropuncture. In addition, transgenic mice with 1-4 copies of the angiotensinogen gene will be subjected to UUO or sham operation. Renal tubular cell disruption (determined by focal contact distribution) and apoptosis (determined by flow cytometry and TUNEL) and their modulators (transforming growth factor-beta 1 , clusterin, and bc1-2) will be examined by analysis of mRNA and protein distribution by immunohistochemistry. Renal interstitial myofibroblast transformation and interstitial fibrosis will also be determined. These studies will elucidate the mechanisms by which the renin-angiotensin system regulates the renal cellular responses to UUO, and may lead to new interventions to avert progression of renal insufficiency in patients with obstructive nephropathy.