KININS ROLE IN MESANGIAL CELL PROLIFERATION

本提案的总体目标是探讨 激动素在系膜细胞增殖中的作用及其特性 参与调节这些事件的信号通路。渐增 有证据表明，肾小球系膜细胞增殖在肾小球疾病中起重要作用。 系膜细胞肥大的发病机制 增生和基质堆积最终可能导致 肾小球硬化。启动核扩散的信号并不是 虽然牵涉到一些调解人，但定义明确。我们 已经积累的证据表明肾脏激肽释放酶-激动素系统在 糖尿病和膳食蛋白对肾脏血流动力学的影响。一个 肾激肽释放酶和激动素作为系膜细胞生长因子的作用 还没有探索过扩张。我们最近的初步数据显示， 第一次，激动素直接增加DNA合成，诱导 血管平滑肌中癌基因表达与MAP-K活性的关系 并刺激胞浆和胞核的酪氨酸磷酸化。 系膜细胞中的蛋白质。因此，我们建议调查 激肽在肾小球系膜细胞增殖中的作用 激动素在细胞内传播其作用的途径 从细胞表面到细胞核。我们将：检验激动素的假设 促进肾小球系膜细胞增殖。要做到这一点，我们将 确定激动素是否诱导系膜细胞肥大和/或增殖 通过评估激肽对蛋白质和DNA合成的影响，细胞 存活率和细胞数量。我们将评估内生代是否 肾小球系膜细胞中一氧化氮或二十烷基类化合物对生长的调节 激动素的促进作用。鉴定早期应答的原癌基因 (c-myc、c-jun、c-fos)。 评估激活蛋白(AP-1)的转录激活 1)复合体通过激肽参与核信号转导。刻画 激动素-受体相互作用的信号通路(S) 刺激系膜细胞生长。我们将鉴定细胞质和 激动素可能被磷酸化的核蛋白 刺激。具体来说，我们将研究pp/60c的磷酸化- SRC、微管蛋白、MAPK和c-jun。确定MAP-K是否为 激动素的反应而激活，如果是这样的话，MAP-K是否易位 从细胞质到细胞核。

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.