NITRIC OXIDE AND ENDOTHELIN INTERACTIONS IN KIDNEY

一氧化氮(NO)和内皮素-1(ET-1)最初被认为是血管内皮细胞衍生因子，现在被认为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被公认为是一种重要的血管扩张剂，但也似乎调节着多种功能，包括炎症、神经传递、细胞生长和增殖以及上皮运输。后者包括抑制肾脏集合管的钠重吸收。虽然ET-1是一种强大的血管收缩因子，但它也作为有丝分裂原发挥作用，影响心脏收缩能力，也可能作为利钠药影响肾小管功能。尽管NO和ET-1大量存在于肾上皮细胞中，但人们对NO和ET-1影响肾小管功能的情况知之甚少。我们推测，在内髓集合管和直肠血管系统中，NO和ET-1的产生之间存在自分泌或旁分泌反馈环。此外，在DOCA-盐性高血压等实验性肾功能障碍模型中，ET-1和NO的活性可能增加，以促进钠的排泄。拟议研究的总体目标是确定NO和ET-1在肾脏集合管中的相互作用。我们认为，ET-1在刺激集合管内NO的产生以应对盐负荷增加方面起重要作用。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活性和随后NO的产生。这一建议的具体目的如下：1.验证ETB受体通过产生NO来调节钠排泄的生理变化的假说。2.探讨ET-1介导集合管产生NO的机制。3.探讨DOCA盐介导的NO产生的病理生理变化机制。

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.