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Molecular mechanism on the maturation of tissue oxygen supply system

组织供氧系统成熟的分子机制

基本信息

批准号：
15590186
负责人：
KOSAKA Hiroaki
金额：
$ 1.98万
依托单位：
Kagawa University, Faculty of Medicine
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (C)
财政年份：
2003
资助国家：
日本
起止时间：
2003 至 2004
项目状态：
已结题

项目摘要

Maturation of tissue oxygen supply system is an important issue to supply oxygen to tissues after tissue injury or vascular obstruction. Sphingosine 1-Phosphate, S1P is a lipid mediator derived from platelets and is supposed to be involved in the angiogenesis and its maturation through its G-protein-coupled S1P1 receptor. We examined whether ROS affects S1P1 receptor expression. The results suggest ROS seems to be involved, however, we must now resolve the induction mechanism. The other studies concerning ROS and pathophysiologic state we did is as follows ; We detected that high salt loading for 4 weeks increased excretion of H_2O_2 in urine of Dahl salt sensitive rats, NADPH-dependent superoxide producing activity in enal cortex, urinary 8-isoprostane and thromboxane B_2 excretion, and decreased plasma NO end products, which were counteracted by L-arginine supplement. We examined an increase in the expressions of NADPH oxidase subunits, gp91phox and p47phox, mRNA abundance with RT-PCR in renal cortex, which was counteracted with oral L-arginine supplement. Western blot revealed that high-salt loading increased gp9lphox protein, which was counteracted by L-arginine supplement both in the total homogenates and in the membrane fractions. High-salt loading powerfully increased p47phox protein, which was distinctly counteracted by L-arginine supplement only in the membrane fractions. These results disclosed that high salt loading causes a deficiency in available L-arginine for NO sythases and induces NADPH oxidase activation in the renal cortex of DS rats, which were counteracted by L-arginine supplement. Superoxide production in the renal cortex of DS rats will accelerate sodium reabsorption and hypertension, since NO inhibits sodium reabsorption in the cortical collecting duct and superoxide rapidly eliminates NO.

组织供氧系统的成熟是组织损伤或血管阻塞后组织供氧的重要问题。sphingosin 1-Phosphate （S1P）是一种源自血小板的脂质介质，通过其g蛋白偶联S1P1受体参与血管生成及其成熟。我们检测了ROS是否影响S1P1受体的表达。结果表明活性氧似乎参与其中，然而，我们现在必须解决诱导机制。我们所做的其他关于ROS与病理生理状态的研究如下；我们发现，高盐负荷4周后，达尔盐敏感大鼠尿液中H_2O_2的排泄量增加，肾皮质nadph依赖性超氧化物生成活性增加，尿8-异前列腺素和凝血素B_2的排泄量增加，血浆NO终产物减少，而l -精氨酸的补充可抵消这一作用。我们用RT-PCR检测了肾皮质NADPH氧化酶亚基gp91phox和p47phox mRNA丰度的增加，口服l -精氨酸补充剂可以抵消这种增加。Western blot结果显示，高盐负荷增加了gp9lphox蛋白，但在总匀浆和膜组分中均被补充l -精氨酸抵消。高盐负荷显著增加了p47phox蛋白，但仅在膜组分中，添加l -精氨酸可明显抵消p47phox蛋白。这些结果表明，高盐负荷导致DS大鼠肾皮质一氧化氮合酶可用l -精氨酸缺乏，诱导NADPH氧化酶激活，而补充l -精氨酸可抵消这一作用。DS大鼠肾皮质产生的超氧化物会加速钠的重吸收和高血压，因为NO抑制皮质收集管中的钠重吸收，而超氧化物会迅速消除NO。