VASCULAR DYSFUNCTION IN DIABETES: GENES AND HORMONES

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 肾素-血管紧张素系统是容量和钠稳态的主要调节器。 该系统调节的紊乱导致病理状态，包括高血压和体液平衡紊乱。 对该项目至关重要的是近二十年来认识到内分泌和旁分泌/自分泌肾素-血管紧张素系统不一定平行调节。 因此，循环中的肾素-血管紧张素系统的正常反应或功能不一定与组织（局部）肾素-血管紧张素系统的正常功能相关。 就本建议而言，最重要的组织系统是肾脏和血管系统内的组织系统。 我们的初步数据（详见下文）有力地支持了NIDDM患者局部（肾）肾素-血管紧张素系统活性不适当增加的观点。 在评估病理状态下肾素-血管紧张素系统的潜在作用时，一个混杂变量是进行评估时的钠和钾稳态状态。 在正常个体中，钠限制降低血管对外源性AngII输注的反应。 无论是评估全身升压反应性还是局部血管床上的AngII活性，即，肾血流量 钠限制对肾上腺对AngII的反应具有相反的作用。 在某些情况下，已经证明这种钠介导的靶组织反应性调节不会发生。 因此，在任何病理过程中评估肾素-血管紧张素系统的作用的一个重要因素是确定钠摄入对每个靶组织反应的影响。 饮食钠摄入量的改变也提供了评估和比较慢性高环境AngII水平（低钠饮食）与低AngII水平（高钠饮食）的影响的机会。 然后可以将对这种方法的反应与在短时间内外源性施用AngII诱导的急性变化进行比较。 特定靶组织对慢性与急性肾素-血管紧张素系统操作的反应不一定彼此平行。除了其在调节血管和激素反应中的传统作用外，AngII还具有许多其他作用，包括促有丝分裂和促生长活性。 它还可以直接或间接改变多种基因的表达。 对本项目重要的是AngII在三个方面的作用：血管系统，特别是改变血压和肾和外周血流量;其在调节胰岛素敏感性中的作用;以及其对派-1血浆水平和基因表达的修饰。 在正常个体中，钠负荷不仅增加全身性升压反应，而且增强肾血流量对AngII的减少，同时减少醛固酮反应。 钠负荷也增加基础肾血流量，可能继发于钠摄入介导的AngII生成减少。 在高血压患者中，对AngII的升压反应通常增强，而肾血管反应通常降低，与钠摄入无关。 然而，特定个体的反应是高度可变的。如果将患者分为低和正常/高肾素亚组，则低肾素患者通常具有增强的血管和肾上腺反应，其通过钠摄入水平进行调节。 肾血流量水平趋于高，但未超出正常范围，肾血管对AngII的反应趋于正常或略有增加。 在正常/高肾素高血压的一个亚组（非调节剂）中，钠摄入不调节血管，特别是肾血管或肾上腺对AngII的反应。 因此，高钠饮食和低钠饮食都会增加升压反应，并且不受钠摄入量的影响。 肾血流量不随膳食钠负荷增加而增加（因此低于正常值），并且其对输注AngII的反应不受钠摄入的影响（因此在高钠摄入时低于正常值）。 此外，高钠饮食的血浆肾素活性（PRA）水平低于正常水平。 在这个高血压亚组中，通过给予血管紧张素转换酶抑制剂（ACEI）来纠正对饮食钠负荷和AngII的肾血流反应的改变，这表明局部AngII的产生增加会产生这种缺陷。 我们认为这与目前的建议有关。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. The renin-angiotensin system is a major regulator of volume and sodium homeostasis. Derangements in the regulation of this system lead to pathologic states, including hypertension and disorders of fluid balance. Of critical importance for this project has been the recognition for nearly two decades that there are both endocrine and paracrine/autocrine renin-angiotensin systems which are not necessarily regulated in parallel. Thus, normal responses or function of the circulating renin-angiotensin system is not necessarily associated with normal function of the tissue (local) renin-angiotensin systems. For the purposes of this proposal, the most important tissue systems are those within the kidney and the vascular system. Our preliminary data (detailed below) strongly supports the concept that there is inappropriately increased activity of the local (renal) renin-angiotensin system in NIDDM. A confounding variable in the evaluation of the potential role of the renin-angiotensin system in pathologic states is the state of sodium and potassium homeostasis at the time an evaluation is performed. In normal individuals, sodium restriction reduces vascular responses to the infusion of exogenous AngII. This is true whether one assesses systemic pressor responsiveness or AngII's activity on a local vascular bed, i.e., renal blood flow. Sodium restriction has the opposite effect on adrenal responses to AngII. In some conditions, it has been documented that this sodium-mediated modulation of target tissue responsiveness does not occur. Thus, an important element in assessing the role of the renin-angiotensin system in any pathologic process is to determine the influence of sodium intake on each target tissue's response. Modification of dietary sodium intake also provides the opportunity to assess and compare the effects of chronic, high ambient AngII levels (low sodium diet) versus low AngII levels (high sodium diet). Responses to this approach then could be compared to acute changes induced by the exogenous administration of AngII over a short period of time. Responses of a particular target tissue to chronic versus acute manipulations of the renin-angiotensin system do not necessarily parallel each other. In addition to its traditional role in modifying vascular and hormonal responses, AngII has a number of other effects including mitogenic and growth-promoting activity. It also can directly or indirectly modify expression of a variety of genes. Of importance to the present project are AngII's effects in three areas: the vascular system, specifically modifying blood pressure and renal and peripheral blood flow; its role in regulating insulin sensitivity; and its modification of PAI-1 plasma levels and gene expression. In normal individuals sodium loading not only increases the systemic pressor responses but also enhances the decrement in renal blood flow to AngII , while it reduces aldosterone responses. Sodium loading also increases basal renal blood flow, probably secondary to the sodium intake-mediated reduction in AngII production. In patients with hypertension, pressor responses to AngII are usually enhanced, while renal vascular responses are normally reduced, independent of sodium intake. However, the response in a specific individual is highly variable. If patients are grouped into low and normal/high renin subgroups, low renin patients generally have both an enhanced vascular and adrenal response which is modified by the level of sodium intake. Renal blood flow levels tend to be high, but are not out of the normal range and renal vascular response to AngII tends to be normal or slightly increased. In one subgroup (non-modulators) of normal/high renin hypertensives, sodium intake does not modulate vascular, particularly renal vascular, or adrenal responses to AngII. Thus, pressor responses are increased on both high and low sodium diets and are not modified by sodium intake. Renal blood flow does not increase with dietary sodium loading (therefore is lower than normal), and its response to infused AngII is not modified by sodium intake (therefore it is less than normal on the high sodium intake). Furthermore, the plasma renin activity (PRA) levels on the high sodium diet, if anything, are lower than normal. The altered renal blood flow responses to dietary sodium loading and AngII in this hypertensive subgroup is corrected by the administration of an angiotensin converting enzyme inhibitor (ACEI), suggesting that increased local production of AngII produces this defect. We believe this is relevant to the current proposal.