Angiotensin II, TGF-beta, and the podocyte in diabetes

血管紧张素 II、TGF-β 和糖尿病中的足细胞

基本信息

批准号：
7576866
负责人：
SHELDON CHEN
金额：
$ 32.97万
依托单位：
NORTHWESTERN UNIVERSITY AT CHICAGO
依托单位国家：
美国
项目类别：
财政年份：
1992
资助国家：
美国
起止时间：
1992-02-01 至 2012-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7576866
关键词：
Albumins Albuminuria Angiotensin II Cells Collagen Type IV Data Development Diabetes Mellitus Diabetic Nephropathy Down-Regulation EGF gene Endothelial Cells Event Extracellular Matrix Extravasation Filtration Functional disorder Genetic Recombination Glomerular Capillary Glucose Homeostasis Hyperglycemia In Vitro Individual Integrin alpha3 Integrins Kidney Kidney Diseases Knock-out Lesion Mediating Mediator of activation protein Metabolic Mus Pathogenesis Pathway interactions Permeability Plasma Proteins Play Production Proteins Proteinuria Receptor Signaling Relative (related person)Research Personnel Rodent Role Signal Pathway Signal Transduction Pathway Stimulus Structure Structure of glomerular mesangium System Transforming Growth Factor beta Transforming Growth Factors Transgenic Mice Up-Regulation Vascular Endothelial Growth Factor Receptor Vascular Endothelial Growth Factor Receptor-1 Vascular Endothelial Growth Factors autocrine cytokine diabetic glomerular basement membrane glomerular endothelium human TGFBR2 protein in vivo non-diabetic novel paracrine podocyte programs receptor research study response slit diaphragm

项目摘要

DESCRIPTION (provided by applicant): The podocyte synthesizes a major portion of the glomerular basement membrane (GBM) to which it anchors via the alphabeta31 integrin, and it maintains the integrity of the filtration barrier that restricts the permeability of proteins. Podocyte dysfunction contributes greatly to the pathogenesis of diabetic glomerulopathy, as reflected by altered GBM composition, decreased podocyte number, and albuminuria. The mechanisms of these changes are incompletely understood, but up-regulation of Vascular Endothelial Growth Factor (VEGF) production by the podocyte may be implicated. The target cell of podocyte-derived VEGF is believed to be the glomerular endothelium, but exciting recent data showing that podocytes possess functional VEGF receptor(s) strongly suggest that VEGF can act on the podocyte itself in an autocrine loop. In fact, over activity of this VEGF loop can exert untoward effects on the podocyte by stimulating production of alpha3 (IV) collagen and decreasing expression of the alpha3 integrin subunit. These cell-matrix interactions may contribute to GBM thickening, podocyte detachment/loss, and altered macromolecular permeability. Our hypothesis is that high levels of intrarenal Angiotensin II and Transforming Growth Factor-( TGF-beta), two of the principal culprits in diabetic kidney disease, cause podocyte overproduction of VEGF that in turn acts in an autocrine loop to promote GBM thickening, cell detachment and albuminuria. Aim 1 will examine the mechanisms whereby diabetic mediators, notably Angiotensin II, stimulate VEGF expression in differentiated mouse podocytes and assess the intermediary role of the up-regulated TGF-beta/Smad pathway in accentuating VEGF expression. Aim 2 will delve into the mechanisms of how the up-regulated EGF autocrine loop causes collagen IV stimulation and a3(1 integrin suppression in podocytes; the VEGF receptor(s) involved and the downstream signal transduction pathways will be elucidated. Aim 3 will explore with in vivo experiments the extent to which individual cytokine systems participate in the development of albuminuria and other lesions of diabetic glomerulopathy; kidney structure and function will be examined in diabetic vs. non-diabetic transgenic mice produced by Cre/LoxP recombination to yield podocyte-specific knockouts of candidate signaling receptors that engage Angiotensin II, TGF-beta, and VEGF (i.e., AT1A, TGF-beta type II receptor, and VEGFR-l/Flt-1, respectively). Selectively ablating the ability of glomerular podocytes to respond to each of these relevant stimuli will allow us to dissect the relative contribution of these systems to podocyte dysfunction in diabetes.

描述（由申请人提供）：Podocyte合成了肾小球基底膜（GBM）的主要部分，其通过Alphabeta31整合素锚定，并保持过滤屏障的完整性限制蛋白质的渗透性。足细胞功能障碍对糖尿病性肾小球病的发病机理有很大贡献，如GBM组成改变，足细胞数量降低和蛋白尿所反映的。这些变化的机制尚不完全理解，但是可能涉及到足细胞对血管内皮生长因子（VEGF）产生的上调。据信，足细胞衍生的VEGF的靶细胞被认为是肾小球内皮，但令人兴奋的最近数据表明，足细胞具有功能性VEGF受体（S）强烈表明VEGF可以在自身分泌循环中作用于足细胞本身。实际上，这种VEGF回路的活性可以通过刺激α3（IV）胶原蛋白的产生并降低alpha3整合素亚基的表达来对足细胞发挥不良影响。这些细胞矩阵相互作用可能有助于GBM增厚，足细胞脱离/损失和大分子渗透性改变。我们的假设是，高水平的肾内血管紧张素II和转化生长因子（TGF-β），这是糖尿病肾脏疾病中的两个主要罪魁祸首，导致VEGF的Podocyte过量产生，从而产生了自身分泌循环，以促进GBM厚度，细胞增厚，细胞分离和蛋白尿素。 AIM 1将检查糖尿病介质（尤其是血管紧张素II）刺激分化小鼠足细胞中的VEGF表达的机制，并评估上调TGF-beta/smad途径在强调VEGF表达中的中介作用。 Aim 2 will delve into the mechanisms of how the up-regulated EGF autocrine loop causes collagen IV stimulation and a3(1 integrin suppression in podocytes; the VEGF receptor(s) involved and the downstream signal transduction pathways will be elucidated. Aim 3 will explore with in vivo experiments the extent to which individual cytokine systems participate in the development of albuminuria and other lesions of糖尿病性肾小球病；将在CRE/LOXP重组产生的糖尿病和非糖尿病的转基因小鼠中检查肾脏结构和功能分别为肾小球足细胞响应这些相关刺激的能力有选择性地消除了这些系统对这些系统对糖尿病中podocyte功能障碍的相对贡献的能力。

项目成果

期刊论文数量（17）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

The nephritogenic T cell response in murine chronic graft-versus-host disease.

小鼠慢性移植物抗宿主病中的致肾病 T 细胞反应。

DOI：
发表时间：
1998
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
0
作者：
Meyers,CM;Tomaszewski,JE;Glass,JD;Chen,CW
通讯作者：
Chen,CW

Renal tubular basement membrane and collagen type IV in diabetes mellitus.

DOI：
10.1038/ki.1993.19
发表时间：
1993
期刊：
Kidney international
影响因子：
19.6
作者：
F. Ziyadeh
通讯作者：
F. Ziyadeh

Effects of glycated albumin on mesangial cells: evidence for a role in diabetic nephropathy.

糖化白蛋白对系膜细胞的影响：在糖尿病肾病中作用的证据。

DOI：
10.1007/bf00926830
发表时间：
1993
期刊：
Molecular and cellular biochemistry
影响因子：
4.3
作者：
Ziyadeh,FN;Cohen,MP
通讯作者：
Cohen,MP

Effects of Tumor Necrosis Factor-α on Podocyte Expression of Monocyte Chemoattractant Protein-1 and in Diabetic Nephropathy.

DOI：
10.1159/000369576
发表时间：
2015-01
期刊：
Nephron extra
影响因子：
0
作者：
Chung CH;Fan J;Lee EY;Kang JS;Lee SJ;Pyagay PE;Khoury CC;Yeo TK;Khayat MF;Wang A;Chen S
通讯作者：
Chen S

Abnormalities in signaling pathways in diabetic nephropathy.