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Cellular and molecular anaylsis of glomerular and tubular functions in hypertension

高血压肾小球和肾小管功能的细胞和分子分析

基本信息

批准号：
07457237
负责人：
ABE Keishi
金额：
$ 4.61万
依托单位：
Tohoku University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (B)
财政年份：
1995
资助国家：
日本
起止时间：
1995 至 1996
项目状态：
已结题

项目摘要

Glomerular and tubular functions are important for homeostasis of body fluid and electrolytes, and hence for the regulation of systemic blood pressure. In this project we employed an in vitro preparation in which microdissected afferent arterioles, a vascular segment crucial to glomerular hemodynamics, are perfused at a controlled pressuse. In addition, the role of prostaglandins were studied using various molecular and cellular biological approaches.1) We studied the effect of 20-hydroxyeicosatetraenoic acid (20-HETE) in isolated microperfused rabbit afferent arterioles. We found that elevated vasal tone is required for 20-HETE to exert its vasoconstrictor action, which is endothelium-dependent and is partially mediated by cyclooxygenase products. In SHR,elevated renal 20-HETE production and increased afferent arteriolar tone co-exist during development of hypertension, with their synergistic actions contributing to the pathogenesis of hypertension.2) The calcium antagonist is most wi … More dely used for treatment of hypertension. We found that calcium antagonists dilate afferent arterioles preconstricted with norepinephrine. Such dilation would render glomerular capillary pressure dependent on systemic blood pressure. Thus, in order for calcium antagonists to exert renoprotective effect by lowing glomerular capillary pressure, systemic blood pressure should be well controlled.3) Studies with microdissected nephron segments have demonstrated that PGs and produed mainly in the vasculature including the glomerulus and collecting tubules. We cloned cDNA of the EP3 receptors, subtype of PGE2 receptor, from the rat kidney, and analyzed its intrarenal distribution and signal transduction mechanism. We found that mRNA of the EP3 receptors was expressed in the distal nephron, including the thick ascending limb and cortical collecting ducts, while their subtype EP3A and EP3B receptors were coupled to a decrease in intracellular cAMP and an increase in Ca2+ respectively, both of which are known to inhibit tubular transport. Thus the PG system appears to function at the site or vicinity of production, controlling water and electrolyte balances. Less

肾小球和肾小管功能对于体液和电解质的动态平衡非常重要，因此对于全身血压的调节也很重要。在这个项目中，我们采用了一种体外制备，其中显微解剖的传入小动脉，血管节段的肾小球血流动力学至关重要，灌注在一个控制的压力。此外，我们还从分子和细胞生物学角度研究了20-羟基二十碳四烯酸（20-hydroxyyeicosatetraenoic acid，20-HETE）对家兔离体微灌注血管的影响。我们发现，20-HETE发挥其血管收缩作用，这是内皮依赖性的，部分是由环氧合酶产物介导的，需要血管紧张度升高。在SHR中，肾20-HETE产生的增加和传入小动脉张力的增加在高血压的发展过程中同时存在，它们的协同作用有助于高血压的发病。 ...更多信息用于治疗高血压。我们发现，钙拮抗剂扩张传入小动脉预收缩与去甲肾上腺素。这种扩张会使肾小球毛细血管压力依赖于全身血压。因此，要使钙拮抗剂通过降低肾小球毛细血管压力发挥肾脏保护作用，就必须控制好全身血压。3）显微肾单位研究表明，PGs主要在肾小球和集合管等血管系统产生。我们从大鼠肾脏中克隆了前列腺素E2受体亚型EP 3受体的cDNA，并分析了其在肾内的分布和信号转导机制。我们发现，EP 3受体的mRNA表达在远端肾单位，包括厚的升支和皮质集合管，而它们的亚型EP 3A和EP 3B受体分别与细胞内cAMP的减少和Ca 2+的增加偶联，这两者都是已知的抑制肾小管转运。因此，PG系统似乎在生产现场或附近发挥作用，控制水和电解质平衡。少