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.
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