NITRIC OXIDE AND ENDOTHELIN INTERACTIONS IN KIDNEY

一氧化氮（NO）和内皮素-1（ET-1）最初被鉴定为内皮源性因子，现在已知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。NO是一种重要的血管扩张剂，但似乎也调节多种功能，包括炎症，神经传递，细胞生长和增殖，上皮运输。 后者包括抑制肾脏集合管中的Na重吸收。 虽然ET-1是一种强有力的血管收缩剂，但它也起有丝分裂原的作用，影响心脏收缩力，并且还可以作为利尿钠剂影响肾小管功能。 虽然存在于肾上皮细胞内的丰富的量，非常少的是知道的情况下，NO和ET-1可能会影响肾小管功能。 我们推测，一个自分泌或旁分泌反馈回路之间存在的NO和ET-1的生产内髓集合管和直小血管系统。此外，在DOCA-盐高血压等肾功能不全的实验模型中，ET-1和NO的活性可能增加以促进Na排泄。 拟议研究的总体目标是确定NO和ET-1之间的相互作用在收集管的肾脏。 我们建议，ET-1起着至关重要的作用，在刺激肾NO的生产在集合管内响应增加盐负荷。 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活性和随后的NO产生。 为了验证ETB受体通过NO的产生介导Na排泄的生理变化的假设。 2. 探讨ET-1介导的集合管NO生成的机制。3. 确定DOCA盐介导的NO产生的病理生理变化的机制。

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.