ANGIOTENSIN II AND NEPHROGENESIS IN VITRO

血管紧张素 II 和体外肾发生

• 批准号: 2614163
• 负责人: TERI J MAUCH
• 金额: $ 11.42万
• 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/2614163
• 关键词: ACE inhibitors; angiotensin II; antisense nucleic acid; apoptosis; cell proliferation; embryo /fetus tissue /cell culture; flow cytometry; growth factor receptors; 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异常引起的 肾脏生长（发育不良）。 虽然胎儿肾脏发育已 从形态学上描述，这些背后的分子机制 变化很大程度上是未知的。血管紧张素 II (AII)，血液调节剂 压力和有效的生长因子，是关键角色的主要候选人 参与胎儿肾发生的调节。 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，包括颅骨异常 发育和肾发育不良。 受影响的婴儿需要透析和 移植以获得长期生存。 我们假设增长 AII 调节胎儿肾脏发育的因素的影响，并且这些 即使胎儿血流没有改变，也会发生动作。 无论 AII缺乏直接导致肾发育不良或继发性 生长因子的作用尚未确定。 后者是 可能是因为 AII 上调了其他几种已知的生长因子 对调节肾脏发育具有重要意义。 初步研究中 使用培养的全大鼠后肾，从混杂的母体中分离出来 影响，我们发现 a) AII 刺激输尿管芽分支，b) ACE-I和1型AII受体阻断引起下降和异常 分支和肾小球发生，而 c) 2 型 AII 受体拮抗作用 增加分支和肾小球生成。 我们建议进行实验 批判性地定义了 AII 在肾发生中的多重作用。 具体目标 1. 检验胎儿肾发生是 受 AII 生长因子效应调节，其中 1 型 (AT1) 受体发挥促进生长作用，2 型 (AT2) 受体 a 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的假设 增殖和凋亡，并将这些变化与改变相关联 形态发生。 具体目标 3. 确定 AII 是否调节 直接影响肾发生，或者其作用是否由 有效的生长调节剂转化生长因子β (TGFbeta) 和 已知血小板衍生生长因子 (PDGF) 均由 AII 诱导。