Cellular Mechanisms of Renal Interstitial Fibrosis

肾间质纤维化的细胞机制

• 批准号: 8492074
• 负责人: JEFFREY L BARNES
• 金额: $ 26.49万
• 依托单位: UNIVERSITY OF TEXAS HLTH SCIENCE CENTER
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-07-01 至 2015-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8492074
• 关键词: 1-Phosphatidylinositol 3-Kinase; 4-ethoxymethylene-2-phenyl-2-oxazoline-5-one; Angiotensin Receptor; Antisense Oligonucleotides; Attention; Biochemical; Biological Assay; Blood Vessels; Cell Proliferation; Cell physiology; Cells; Chronic Kidney Failure; Data; Development; Dialysis procedure; Dominant-Negative Mutation; Early treatment; Event; Family; Fibroblasts; Fibrosis; Generations; Gleevec; Growth Factor; Immunofluorescence Immunologic; In Situ Hybridization; In Vitro; Injection of therapeutic agent; Kidney; Kidney Diseases; Kidney Failure; Kidney Transplantation; Knockout Mice; Label; Lead; Location; MADH2 gene; MAP Kinase Gene; MAPK3 gene; Mitogen-Activated Protein Kinase 3; Modeling; Monomeric GTP-Binding Proteins; Myofibroblast; Oxidases; PDGFRB gene; Pathway interactions; Phosphorylation; Platelet-Derived Growth Factor; Protein Isoforms; Reactive Oxygen Species; Receptor Activation; Receptor Signaling; Regulation; Relative (related person); Research; Role; Signal Pathway; Signal Transduction; Signaling Protein; Staging; Structure; Transforming Growth Factor beta Receptors; Tubular formation; Vascular Diseases; acetovanillone; autocrine; cell motility; cell type; design; glomerulosclerosis; in vivo; inhibitor/antagonist; insight; intercellular communication; interstitial; migration; public health relevance; receptor; research study; rho

DESCRIPTION (provided by applicant): Progression of renal disease leads to common consequences including interstitial fibrosis, glomerulosclerosis, vascular narrowing, and renal failure, ultimately requiring dialysis or renal transplantation. The kidney myofibroblast is the cell type most responsible for matrix accumulation during renal fibrosis. Although there is a large amount of data on mechanisms of interstitial myofibroblast matrix synthesis late in the course of renal fibrosis, information on the earliest cellular events involving myofibroblast encroachment into the perivascular and interstitial spaces prior to matrix accumulation is lacking. Experiments are proposed to examine mechanisms of myofibroblast encroachment (migration and proliferation) in a model of accelerated renal fibrosis in which myofibroblasts first originate from perivascular and periglomerular regions. Our central hypothesis is: Activation of PDGFR-2 and TGF-beta receptor induces fibroblast migration and proliferation into the peritubular interstitium via Rho/ROCK modulated ROS generation and transduction of PI3-kinase/Akt, MAPK (ERK1/2) signaling pathways early during the progression of renal fibrosis. The following aims are set: Aim 1. NAD(P)H oxidase-derived ROS are involved in myofibroblast interstitial encroachment early during the course of kidney fibrosis; Aim 2. ROS-induced interstitial myofibroblast migration, proliferation and matrix synthesis is a consequence of PDGFR-2 and TGF- beta receptor activation; Aim 3. ROS generation through PDGFR-2 and TGF-2 receptor regulate SMAD2/3, Rho/ROCK, ERK1/2 and Akt signaling cascades, initiating interstitial myofibroblast migration, proliferation, and matrix synthesis. PDGF BB and TGF2-1 initiate ROS generation in vascular disease. Experiments are designed to critically examine a role for NAP(P)H oxidase and associated phox subunits in ROS generation, PDGFR-2 and TGF-2 receptor activation and signaling pathways on myofibroblast migration, proliferation and matrix synthesis in vitro and in vivo. Specifically, a role for the NAD(P)H oxidase pathway (Nox2 and Nox4 and phox subunits) will be examined in PDGFR-2 and TGF-2 receptor transduction of SMADs, Rho/ROCK, PI3K, and ERK1/2 regulation of activation of kidney myofibroblast. These studies will provide much needed insight on mechanisms of myofibroblast activation during the early stages of renal fibrosis. PUBLIC HEALTH RELEVANCE: To date, the majority of research on renal interstitial fibrosis has focused on late changes associated with matrix accumulation, with little attention on early events of myofibroblast encroachment (migration and proliferation) into the interstitium. Understanding the mechanisms of myofibroblast encroachment before fibrosis occurs could lead to new therapies in the early treatment of chronic renal disease. This application focuses on a role for reactive oxygen species (ROS) in renal myofibroblast encroachment early during the initial stages of fibrosis.

描述（由申请人提供）：肾脏疾病进展导致常见后果，包括间质纤维化、肾小球硬化、血管狭窄和肾衰竭，最终需要透析或肾移植。肾肌成纤维细胞是在肾纤维化期间最负责基质积聚的细胞类型。虽然有大量的数据间质肌成纤维细胞基质合成的机制在肾纤维化的过程中，最早的细胞事件涉及肌成纤维细胞侵入血管周围和间质空间之前，基质积累的信息是缺乏的。实验提出了检查机制的肌成纤维细胞侵蚀（迁移和增殖）在加速肾纤维化的模型中，肌成纤维细胞首先起源于血管周围和肾小球周围区域。我们的中心假设是：PDGFR-2和TGF-β受体的激活通过Rho/ROCK调节的ROS产生和PI 3-激酶/Akt、MAPK（ERK 1/2）信号通路的转导诱导成纤维细胞迁移和增殖进入肾小管周上皮细胞。设定了以下目标：NAD（P）H氧化酶衍生的ROS参与肾纤维化过程早期肌成纤维细胞间质侵犯;目的2。ROS诱导的间质肌成纤维细胞迁移、增殖和基质合成是PDGFR-2和TGF-β受体活化的结果;目的3。通过PDGFR-2和TGF-2受体产生的ROS调节SMAD 2/3、Rho/ROCK、ERK 1/2和Akt信号级联，启动间质肌成纤维细胞迁移、增殖和基质合成。PDGF BB和TGF 2 -1在血管疾病中启动ROS产生。实验旨在严格检查NAP（P）H氧化酶和相关的phox亚基在ROS生成，PDGFR-2和TGF-2受体激活和信号通路对肌成纤维细胞迁移，增殖和基质合成中的作用，在体外和体内。具体而言，将检查NAD（P）H氧化酶途径（Nox 2和Nox 4以及phox亚基）在SMAD的PDGFR-2和TGF-2受体转导、Rho/ROCK、PI 3 K和ERK 1/2调节肾肌成纤维细胞活化中的作用。这些研究将为肾纤维化早期阶段肌成纤维细胞活化机制提供急需的见解。 公共卫生关系：迄今为止，大多数关于肾间质纤维化的研究都集中在与基质积累相关的晚期变化上，很少关注肌成纤维细胞侵入（迁移和增殖）到肾小球的早期事件。了解纤维化发生前肌成纤维细胞侵入的机制可能会导致慢性肾脏疾病早期治疗的新疗法。本申请关注的是活性氧（ROS）在纤维化初始阶段早期肾肌成纤维细胞侵入中的作用。