SMAD SIGNALING IN ANGIOTENSIN II-MEDIATED RENAL FIBROSIS

血管紧张素 II 介导的肾纤维化中的 SMAD 信号传导

• 批准号: 7061191
• 负责人: WILLIAM Evans MITCH
• 金额: $ 32.7万
• 依托单位: BAYLOR COLLEGE OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2005
• 资助国家: 美国
• 起止时间: 2005-05-01 至 2009-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7061191
• 关键词: angiotensin II; chronic renal failure; collagen; embryo /fetus tissue /cell culture; epithelium; fibroblasts; fibrosis; genetically modified animals; kidney cell; laboratory mouse; mitogen activated protein kinase; molecular pathology; protein protein interaction; renal tubule; transcription factor; transforming growth factors

DESCRIPTION (provided by applicant): Ang II plays a pivotal role in the development of end-stage renal disease. It is known that Ang II acts by stimulating TGF-b to mediate renal fibrosis. However, our preliminary studies showed an additional signaling pathway that may be required for renal fibrosis induced by Ang II. We found that Ang II is able to activate the TGF-b signaling pathway, Smad2 and SmadS. This response leads to increased collagen production by two mechanisms: 1) an acute pathway (5-30 minutes) via activation of the ERK/p38 MAP kinases; and 2) a late mechanism (24 hours) that acts through autocrine TGF-b and leads to fibrosis. Furthermore, we also find that mice null for SmadS are protected against renal fibrosis, while mice that are conditionally deleted for Smad2 enhance SmadS signaling and renal fibrosis in response to Ang II. Thus, we hypothesize that Smad signaling is a key to the development of renal fibrosis in response to Ang II. We plan to test this hypothesis and to determine the new role for the Ang Il-Smad signaling pathway in renal fibrosis by pursuing three specific aims. In Aim 1, we will study that Ang II activates Smads via an acute (5-30 mins) ERK/p38 MAPKdependent and a late (20 hrs) classic TGF-b-dependent pathways. In Aim 2, we will dissect the functional role of TGF-b-dependent and independent Smad signaling pathways in Ang ll-induced renal fibrosis in mesangial cells (MC) and tubular epithelial cells (TEC) that do or do not express TGF-b or TbRII, and in conditional TbRII KO mice. In Aim 3, we will dissect the specific role of Smad2 or SmadS in Ang ll-mediated renal fibrosis. This will be examined in mouse embryonic fibroblasts, MC, and TEC that do or do not express Smad2 and SmadS and in SmadS KO and conditional Smad2 KO mice. We expect that the outcomes obtained from this study will support the central hypothesis and provide new insights into the pathogenesis of Ang ll-mediated renal fibrosis and valuable information for the development of new therapeutic strategies to combat renal fibrosis by targeting Smad signaling.

描述（由申请人提供）：血管紧张素II在终末期肾病的发展中起着关键作用。已知Ang II通过刺激TGF-β介导肾纤维化而起作用。然而，我们的初步研究表明，一个额外的信号通路，可能需要为肾纤维化的血管紧张素II诱导。我们发现Ang II能够激活TGF-β信号通路Smad 2和SmadS。这种反应通过两种机制导致胶原蛋白产生增加：1）通过ERK/p38 MAP激酶活化的急性途径（5-30分钟）;和2）通过自分泌TGF-β起作用并导致纤维化的晚期机制（24小时）。此外，我们还发现SmadS缺失的小鼠受到保护免受肾纤维化，而Smad 2条件性缺失的小鼠增强SmadS信号传导和肾纤维化对Ang II的响应。因此，我们推测Smad信号是血管紧张素II引起肾纤维化的关键。我们计划通过以下三个具体目标来验证这一假设，并确定血管紧张素Ⅱ-Smad信号通路在肾纤维化中的新作用。目的1：研究Ang Ⅱ通过急性（5-30 min）ERK/p38 MAPK依赖性途径和晚期（20 h）经典TGF-β依赖性途径激活Smads。在目标2中，我们将剖析TGF-β依赖性和非依赖性Smad信号通路在表达或不表达TGF-β或TbRII的系膜细胞（MC）和肾小管上皮细胞（TEC）中以及在条件性TbRII KO小鼠中Ang II诱导的肾纤维化中的功能作用。在目的3中，我们将剖析Smad 2或SmadS在Ang II介导的肾纤维化中的具体作用。这将在表达或不表达Smad 2和SmadS的小鼠胚胎成纤维细胞、MC和TEC以及SmadS KO和条件性Smad 2 KO小鼠中进行检查。我们期望从该研究获得的结果将支持中心假设，并提供对Ang II介导的肾纤维化的发病机制的新见解和用于开发通过靶向Smad信号传导来对抗肾纤维化的新治疗策略的有价值的信息。