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）：ANG II在末期肾脏疾病的发展中起关键作用。众所周知，ANG II通过刺激TGF-B介导肾纤维化而起作用。但是，我们的初步研究表明，ANG II诱导的肾纤维化可能需要的额外信号通路。我们发现ANG II能够激活TGF-B信号通路，SMAD2和SMADS。这种反应通过两种机制导致胶原蛋白的产生增加：1）通过激活ERK/p38 MAP激酶，急性途径（5-30分钟）； 2）通过自分泌TGF-B起作用并导致纤维化的后期机制（24小时）。此外，我们还发现，SMAD的小鼠无效受到肾纤维化的保护，而对于SMAD2的有条件删除的小鼠会增强SMADS信号传导和肾纤维化，以响应ANG II。因此，我们假设SMAD信号传导是响应ANG II的肾纤维化发展的关键。我们计划检验这一假设，并通过追求三个特定目标来确定肾纤维化中ANG IL-SMAD信号通路的新作用。在AIM 1中，我们将研究ANG II通过急性（5-30分钟）ERK/p38 MAPKDECTENT和晚期（20小时）经典TGF-B依赖性途径激活SMAD。在AIM 2中，我们将剖析ANG LL诱导的肾脏纤维化中TGF-B依赖性和独立的SMAD信号通路的功能作用，这些肾脏纤维化（MC）和肾小管上皮细胞（TEC）（TEC）（TEC）在表达TGF-B或不表达TGF-B或TBRII的功能作用。在AIM 3中，我们将阐述SMAD2或SMADS在ANG LL介导的肾纤维化中的特定作用。这将在做或不表达SMAD2和SMADS以及SMADS KO和条件SMAD2 KO小鼠的小鼠胚胎成纤维细胞，MC和TEC中进行检查。我们预计，从这项研究中获得的结果将支持中心假设，并为ANG LL介导的肾纤维化发病机理和有价值的信息提供新的见解，以开发新的治疗策略，以靶向SMAD信号来对抗肾纤维化。