PATHOPHYSIOLOGY OF THE AGING KIDNEY

描述：肾小球血流动力学变化和血管紧张素II（Ang II） 参与与年龄相关的肾功能变化。衰老大鼠 发展成肾小球毛细血管高血压，阻断血管紧张素11可减缓 年龄相关性肾病然而，肾脏对Ang 11阻断的反应性 随着年龄的增长而下降。三个互补的假设是 建议：首先，可以考虑肾肾素-血管紧张素系统（RAS） 作为两个不同的系统：血管系统（组成血浆和 血管系统，包括肾小球）和肾小管间质系统。第二、 这两个系统随着年龄的增长而变化，不一定是协调的 与适应不良的RAS变化有助于年龄相关的损伤。三是 随着年龄的增长，收缩血管和舒张血管之间的平衡发生了变化 调解人，使前者占主导地位。为了支持这些假设， 申请人发现血浆Ang II水平下降，但肾Ang II水平 II水平（可能是肾小管间质）在老龄大鼠中很高。 此外，老龄大鼠对血管收缩剂表现出更强的肾脏反应， 但对血管扩张刺激无反应。第二种，是一种“以人为本”的精神。 血管收缩剂）可能是迄今为止未被认识到的 年龄相关性肾损伤的发病机制。平衡中的扰动 影响血液动力学，但也导致效应器的变化， 由这些调解人来调解。 有三个具体目标。(1)定位并量化异常 血管和肾小管间质的肾素血管紧张素系统在老化， 通过确定不一致RAS组件处理的位置;（2） 评估长期血管紧张素转换酶 (ACE)相比之下， 与其他抗高血压方案，并通过评估治疗效果 对血流动力学功能和损伤介质的影响;（3）检查 肾多巴胺能系统的活性，及其与 RAS对老年人血流动力学和利钠功能的调节 肾使用一种结合了生理，生化， 免疫组织化学和分子生物学方法应该了解 这个临床上重要但研究不足的问题

DESCRIPTION: Glomerular hemodynamic changes and angiotensin II (Ang II) participate in the age-related changes in renal function. Aging rats develop glomerular capillary hypertension, and blockade of Ang 11 slows age-related nephropathy. However, renal responsiveness to Ang 11 blockade declines in the course of aging. Three complementary hypotheses are proposed: First, the renal renin-angiotensin system (RAS) may be considered as two distinct systems: a vascular system (composing the plasma and vasculature, including glomeruli), and a tubulointerstitial system. Second, these two systems change with aging, not necessarily in coordinated fashion with maladaptive RAS changes contributing to age-related injury. Third, in aging there is a shift in the balance between constrictor and vasodilatory mediators, so that the former predominate. In support of these hypotheses, the applicant has found that plasma Ang II levels fall, but that renal Ang II levels (presumably tubulointerstitial) are high in the aging rat. Furthermore, aging rats exhibit greater renal responses to vasoconstrictors, but not to vasodilator stimuli. Thus, a predominance of Ang II (and other vasoconstrictors) may be a heretofore unrecognized key participant in the pathogenesis of age-related renal injury. Perturbations in the balance affect hemodynamics, but also lead to changes in effectors which are regulated by those mediators. There are three specific aims. (1) To localize and quantify the anomalies of the vascular and tubulointerstitial renin angiotensin systems in aging, by determining the site(s) of discordant RAS component processing; (2) to evaluate the mechanisms by which long-term angiotensin converting enzyme (ACE) inhibition protects against chronic age-related injury, by comparison with other antihypertensive regimens, and by evaluating effects of therapy on hemodynamic function and mediators of injury; and (3) to examine the activity of the renal dopaminergic system, and its interactions with the RAS, in regulation of hemodynamic and natriuretic function in the aging kidney. The use of a combined physiological, biochemical, immunohistochemical, and molecular biologic approach should gain insight into this clinically important but understudied problem.