ANGIOTENSIN II AND NEPHROGENESIS IN VITRO

血管紧张素 II 和体外肾发生

• 批准号: 2904974
• 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/2904974
• 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病是由于 肾生长（发育不良）。 虽然胎儿肾脏的发育 从形态学上描述，这些分子机制 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，是一个关键作用的主要候选人 在胎儿肾发生的调节中。 妊娠晚期的治疗 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， 移植以获得长期生存。 我们假设增长 AII的因子效应调节胎儿肾脏发育，并且这些 甚至在没有改变的胎儿血流的情况下也会发生动作。 是否 AII缺乏直接导致肾发育不良或是否继发 生长因子的作用尚未确定。 后者是 可能是因为AII上调了几种其他已知的生长因子， 在调节肾脏发育中起重要作用。 在初步研究中 使用培养的整个大鼠后肾，分离自混杂母体 影响，我们发现a）AII刺激输尿管芽分支，B） ACE-I和1型AII受体阻断剂可引起细胞凋亡减少和异常。 分支和肾小球形成，而c）2型AII受体拮抗剂 增加分支和肾小球形成。 我们提出实验， 批判性地定义了AII在肾发生中的多重作用。 具体目标1。为了验证胎儿肾形成是 受AII的生长因子效应调节，其中1型（AT1） 受体发挥促生长作用，2型（AT 2）受体发挥促生长作用， 生长抑制或促凋亡作用。 具体目标2。测试 AII信号传导改变导致细胞异常假说 增殖和凋亡，并将这些变化与改变的 形态发生 具体目标3。确定AII是否调节 肾发生直接，或其影响是否介导的 有效的生长调节剂转化生长因子β（TGF β）和 血小板衍生的生长因子（PDGF），两者都已知由AII诱导。