ANGIOTENSIN II AND NEPHROGENESIS IN VITRO

血管紧张素 II 和体外肾发生

• 批准号: 6380042
• 负责人: TERI J MAUCH
• 金额: $ 12.93万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 1998
• 资助国家: 美国
• 起止时间: 1998-07-01 至 2003-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6380042
• 关键词: ACE inhibitors; angiotensin II; angiotensin receptor; antisense nucleic acid; apoptosis; cell proliferation; embryo /fetus tissue /cell culture; flow cytometry; histogenesis; hormone regulation /control mechanism; in situ hybridization; kidney; kidney hyperplasia; laboratory mouse; mitogen activated protein kinase; organ culture; platelet derived growth factor; polymerase chain reaction; receptor expression; renin angiotensin system; transforming growth factors

One-third of end stage renal disease in children results from abnormal renal growth (dysplasia). Although fetal renal development has been described morphologically, the molecular mechanisms underlying these changes are largely unknown. Angiotensin II (AII), a regulator of blood pressure and potent growth factor, is a prime candidate for a key role in the regulation of fetal nephrogenesis. Treatment of late gestation pregnant women with angiotensin converting enzyme inhibitors (ACE-I) has dire consequences for the developing fetus, including abnormal skull development and renal dysplasia. Affected infants require dialysis and transplantation for long-term survival. We hypothesize that growth factor effects of AII modulate fetal renal development, and that these actions occur even in the absence of altered fetal blood flow. Whether AII deficiency directly causes renal dysplasia or whether secondary growth factors are responsible has not been determined. The latter is likely, because AII upregulates several other growth factors known to be important in regulating renal development. In preliminary studies using cultured whole rat metanephroi, isolated from confounding maternal influences, we found that a) AII stimulated ureteric bud branching, b) ACE-I and type 1 AII receptor blockade caused decreased and aberrant branching and glomerulogenesis, while c) type 2 AII receptor antagonism increased branching and glomerulogenesis. We propose experiments to critically define the multiple roles of AII in nephrogenesis. Specific Aim 1. To test the hypothesis that fetal nephrogenesis is regulated by the growth factor effects of AII, with the type 1 (AT1) receptor playing a growth-promoting and the type 2 (AT2) receptor a growth-inhibiting or pro-apoptotic role. Specific Aim 2. To test the hypothesis that altered AII signaling leads to abnormal cell proliferation and apoptosis and to correlate these changes with altered morphogenesis. Specific Aim 3. To determine whether AII modulates nephrogenesis directly, or whether its effects are mediated by the potent growth regulators transforming growth factor beta (TGFbeta) and platelet derived growth factors (PDGF) both known to be induced by AII.

三分之一的儿童终末期肾脏疾病是由异常引起的 肾发育不良(发育不良)。尽管胎儿肾脏发育一直以来 从形态上描述了这些现象背后的分子机制 变化在很大程度上是未知的。血管紧张素II(AII)，一种血液调节剂 压力和强大的增长因素，是关键角色的首选人选 在调节胎儿肾脏发育中起重要作用。妊娠晚期的治疗 服用血管紧张素转换酶抑制剂(ACE-I)的孕妇 对发育中的胎儿造成可怕的后果，包括头骨异常 发育和肾发育不良。受影响的婴儿需要透析和 长期存活的移植。我们假设经济增长 AII调节胎儿肾脏发育的因素作用，这些 即使在胎儿血流没有改变的情况下，也会发生反应。是否 AII缺乏直接导致肾发育不良或继发性 增长因素的责任尚未确定。后者是 很有可能，因为AII上调了其他几个已知的增长因素 在调节肾脏发育方面发挥重要作用。在初步研究中 使用培养的大鼠全后肾，分离自混杂的母体 影响，我们发现a)所有的刺激输尿管芽分支，b) ACE-I和1型AII受体阻断引起的减少和异常 分支和肾小球形成，而c)2型AII受体拮抗 增加分枝和肾小球生成。我们建议进行实验，以 批判性地确定AII在肾脏形成中的多种作用。 具体目标1.检验胎儿肾脏发生是 受AII的生长因子效应调节，类型1(AT1) 促生长受体和2型(AT2)受体 抑制生长或促进细胞凋亡的作用。具体目标2.测试 AII信号改变导致细胞异常的假说 增殖和凋亡，并将这些变化与改变 形态发生。具体目标3.确定AII是否调节 肾直接发生，或其影响是否由 强大的生长调节剂转化生长因子β(TGFbeta)和 血小板衍生生长因子(PDGF)都是由AII诱导的。