KININS ROLE IN MESANGIAL CELL PROLIFERATION

激肽在系膜细胞增殖中的作用

• 批准号: 2145768
• 负责人: AYAD A JAFFA
• 金额: $ 10.06万
• 依托单位: MEDICAL UNIVERSITY OF SOUTH CAROLINA
• 依托单位国家: 美国
• 财政年份: 1995
• 资助国家: 美国
• 起止时间: 1995-07-10 至 2000-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2145768
• 关键词: DNA replication; biological signal transduction; cell cycle proteins; cell population study; cytoplasm; eicosanoids; enzyme activity; immunocytochemistry; kidney cell; kidney hyperplasia; kidney hypertrophy; kinins; laboratory rat; nitric oxide synthase; nucleoproteins; phosphorylation; posttranslational modifications; protein biosynthesis; protooncogene; receptor binding; renal glomerulus; tissue /cell culture; transcription factor; tubulin

The overall objective of the present proposal is to explore the role of kinins in mesangial cell proliferation and to characterize the kinin signaling pathways involved in mediating these events. Increasing evidence indicates that mesangial cell proliferation is important in the pathogenesis of mesangial expansion; mesangial cell hypertrophy, hyperplasia and matrix accumulation may ultimately lead to glomerulosclerosis. The signals which initiate proliferation are not clearly defined although a number of mediators have been implicated. We have accumulated evidence that the renal kallikrein-kinin system mediates the renal hemodynamic changes induced by diabetes and dietary protein. A role for renal kallikrein and kinins as growth factors for mesangial cell expansion has not been explored. Our recent preliminary data, indicate for the first time, that kinins directly increase DNA synthesis, induce oncogene expression and MAP-kinase activation in vascular smooth muscle cells, and stimulate tyrosyl phosphorylation of cytoplasmic and nuclear proteins in mesangial cells. Therefore, we propose to investigate the role of kinins in mesangial cell proliferation and to dissect the intracellular pathways by which kinins propagate their effects from the cell surface to the nucleus. We will: Test the hypothesis that kinins promote proliferation of glomerular mesangial cells. To do this we will determine if kinins induce mesangial cell hypertrophy and/or hyperplasia by assessing the influence of kinins on protein and DNA synthesis, cell viability and cell number. We will evaluate whether endogenous generation of nitric oxide or eicosanoids in mesangial cells modulate the growth promoting effects of kinins. Identify the early response proto-oncogenes (c-myc, c-jun, c-fos) that may be induced in response to kinin challenge. Evaluate whether transcriptional activation of the activator protein (AP- 1) complex contributes to nuclear signaling by kinins. To characterize the signaling pathway(s) that link kinin-receptor interactions to stimulation of mesangial cell growth. We will identify cytoplasmic and nuclear proteins that may be phosphorylated in response to kinin stimulation. Specifically, we will study the phosphorylation of pp/60c- src, tubulin, MAP-kinase and c-Jun. Determine whether MAP-kinase is activated in response to kinin and if so, whether MAP-kinase translocates from the cytoplasm to the nucleus.

本提案的总体目的是探索 肾小球细胞增殖中的基因素，并表征Kinin 介导这些事件涉及的信号通路。 增加 证据表明，肾小球细胞增殖在 肾小球扩张的发病机理；肾小球细胞肥大， 增生和基质积累最终可能导致 肾小球硬化。 引发增殖的信号不是 尽管已经牵涉到许多调解人，但明确定义了。 我们 积累了肾脏Kallikrein-Kinin系统介导的证据 糖尿病和饮食蛋白诱导的肾脏血流动力学变化。 一个 肾脏Kallikrein和Kinin的作用作为肾小球细胞的生长因子 尚未探索扩展。 我们最近的初步数据表明 第一次，Kinin直接增加DNA合成，诱导 血管平滑肌中的癌基因表达和MAP-激酶激活 细胞，并刺激细胞质和核的酪酶磷酸化 肾小球细胞中的蛋白质。 因此，我们建议调查 基因素在肾小球细胞增殖中的作用并剖析 细胞内途径基因素传播了它们的作用 细胞表面到核。 我们将：检验基因素的假设 促进肾小球肾小球细胞的增殖。 为此，我们将 确定运动蛋白是否诱导肾小球肥大和/或增生 通过评估动力素对蛋白质和DNA合成的影响，细胞 生存力和单元格。 我们将评估内源性是否生成 肾小球细胞中的一氧化氮或类花生素的生长 促进运动素的作用。 识别早期反应原始基因 （C-Myc，C-Jun，c-fos）可能会响应Kinin挑战。 评估激活蛋白的转录激活是否（ap-） 1）复合物有助于基因蛋白的核信号传导。 表征 将Kinin受体相互作用与 刺激肾小球细胞生长。 我们将确定细胞质和 响应基因蛋白可能会磷酸化的核蛋白 刺激。 具体而言，我们将研究PP/60C-的磷酸化 SRC，微管蛋白，地图激酶和C-Jun。 确定地图激酶是否是 响应于Kinin的激活，如果是的话，MAP-激酶是否易位 从细胞质到核。