NITRIC OXIDE AND ENDOTHELIN INTERACTIONS IN KIDNEY

一氧化氮和内皮素在肾脏中的相互作用

• 批准号: 6389969
• 负责人: Jennifer S Pollock
• 金额: $ 26.45万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-04-01 至 2003-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6389969
• 关键词: cell line; cellular respiration; dietary sodium; endothelin; enzyme activity; hormone receptor; immunocytochemistry; isozymes; laboratory rat; nephrectomy; nitric oxide; nitric oxide synthase; nutrition related tag; receptor sensitivity; renal tubular transport; renal tubule; saluresis; saluretic

Originally identified as endothelial-derived factors, nitric oxide (NO) and endothelin-1 (ET-1) are now known to be key mediators in a number of physiological and pathophysiological processes related to both vascular and non-vascular functions. NO is well-established as an important vasodilator but also appears to modulate a variety of functions including inflammation, neurotransmission, cell growth and proliferation, and epithelial transport. The latter includes inhibition of Na reabsorption in the collecting duct of the kidney. While ET-1 is a powerful vasoconstrictor, it too, functions as a mitogen, influences cardiac contractility, and also may serve to influence renal tubular function as a natriuretic agent. Although present in abundant quantities within renal epithelia, very little is known about the circumstances in which NO and ET-1 may influence tubular function. We hypothesize that an autocrine or paracrine feedback loop exists between NO and ET-1 production within the inner medullary collecting duct and vasa recta system. Furthermore, in experimental models of renal dysfunction such as DOCA-salt hypertension, the activity of ET-1 and NO may be increased to promote Na excretion. The overall goal of the proposed studies is to determine the interaction between NO and ET-1 in the collecting duct of the kidney. We propose that ET-1 plays an essential role in stimulating renal NO production within the collecting duct in response to increased salt load. Similar to mechanisms that occur in vascular endothelial cells, we predict that stimulation of ETB receptors in the collecting duct cells will increase NOS activity and subsequent production of NO. The specific aims of this proposal are as follows: 1. To test the hypothesis that ETB receptors mediate physiological changes in Na excretion via NO production. 2. To determine the mechanism of ET-1-mediated NO production in the collecting duct. 3. To determine the mechanism of DOCA salt-mediated pathophysiological changes in NO production.

一氧化氮 (NO) 和内皮素-1 (ET-1) 最初被认为是内皮衍生因子，现在已知它们是与血管和非血管功能相关的许多生理和病理生理过程中的关键介质。一氧化氮被认为是一种重要的血管扩张剂，但似乎也能调节多种功能，包括炎症、神经传递、细胞生长和增殖以及上皮运输。 后者包括抑制肾集合管中的 Na 重吸收。 虽然 ET-1 是一种强大的血管收缩剂，但它也可作为有丝分裂原，影响心肌收缩力，并且还可以作为利钠剂影响肾小管功能。 尽管NO和ET-1在肾上皮内大量存在，但人们对NO和ET-1可能影响肾小​​管功能的情况知之甚少。 我们假设内髓集合管和直肠血管系统内 NO 和 ET-1 的产生之间存在自分泌或旁分泌反馈回路。此外，在DOCA盐高血压等肾功能障碍实验模型中，ET-1和NO的活性可能会增加以促进Na排泄。 拟议研究的总体目标是确定肾集合管中 NO 和 ET-1 之间的相互作用。 我们认为 ET-1 在响应盐负荷增加而刺激集合管内肾脏 NO 产生方面发挥着重要作用。 与血管内皮细胞中发生的机制类似，我们预测刺激集合管细胞中的 ETB 受体将增加 NOS 活性以及随后 NO 的产生。该提案的具体目的如下： 1. 检验 ETB 受体通过 NO 产生介导 Na 排泄生理变化的假设。 2. 确定集合管中ET-1介导的NO产生的机制。 3.确定DOCA盐介导的NO产生病理生理变化的机制。