ANGIOTENSIN IN RENAL RESPONSE TO URETERAL OBSTRUCTION

通过干扰肾脏的生长和发育， 尿路梗阻是引起肾功能不全的重要原因之一。 婴儿和儿童的失败。阻塞性肾病也是一种 成人肾功能不全的重要原因。 单方面 输尿管梗阻（UUO）激活肾程序性细胞死亡 （细胞凋亡）和肾素-血管紧张素系统。 这些反应更大 而且新生儿比成人更长。 血管紧张素II（ANG II）刺激转化生长因子β 1和肌成纤维细胞 转化，这可能导致间质纤维化的进展， 梗阻的肾脏出现肾小管萎缩然而，在UUO之后， 在新生大鼠中，外源性ANG II增加肾小管细胞增殖 并减少阻塞肾脏中的细胞凋亡。 我们假设 肾脏产生的ANG II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 建议的研究计划，肾素-血管紧张素系统将有选择地 抑制（依那普利、氯沙坦或PD 123319）或刺激（ANG II） 新生和成年大鼠UUO或假手术。 肾间质 ANG II将通过微透析测量，并且对单个ANG II的反应将通过微透析测量。 肾单位阻塞将通过显微穿刺来确定。 此外，本发明还提供了一种方法， 具有1-4个拷贝的血管紧张素原基因的转基因小鼠将被 进行UUO或假手术。 肾小管细胞破坏 （通过病灶接触分布确定）和细胞凋亡（通过 流式细胞术和TUNEL）及其调节剂（转化生长 factor-beta 1、clusterin和bc 1 -2）将通过mRNA分析进行检测。 免疫组织化学检测蛋白分布。 肾间质 肌成纤维细胞转化和间质纤维化也将是 测定 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， 肾功能不全的患者。

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.