PATHOPHYSIOLOGY OF THE AGING KIDNEY

描述：肾小球血流动力学改变与血管紧张素II(Ang II) 参与与年龄相关的肾功能变化。衰老大鼠 发展为肾小球毛细血管高压，Ang 11的阻断速度减缓 年龄相关性肾病。然而，肾脏对血管紧张素Ⅱ受体拮抗剂的反应性 在老化的过程中衰退。三个互补性假设是 建议：首先，可以考虑肾脏肾素-血管紧张素系统(RAS) 作为两个截然不同的系统：血管系统(组成血浆和 血管系统，包括肾小球)和小管间质系统。第二, 这两个系统随着年龄的增长而变化，但不一定是协调一致的。 适应不良的RAS变化会导致年龄相关的损伤。第三，在 随着年龄的增长，收缩和血管扩张之间的平衡发生了变化 调解人，让前者占主导地位。为了支持这些假设， 申请人发现血浆Ang II水平下降，但肾脏Ang 在衰老大鼠中，II水平(可能是肾小管间质)很高。 此外，衰老的大鼠对血管收缩药表现出更强的肾脏反应， 但对血管扩张剂刺激物不起作用。因此，Ang II(和其他 血管紧张剂)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 影响血流动力学，但也会导致效应器的变化 受这些调解人的监管。 有三个具体目标。(一)对异常情况进行定位量化 血管和间质肾素血管紧张素系统在衰老过程中的变化， 通过确定不协调RAS成分处理的地点(S)；(2) 评价长期血管紧张素转换酶的作用机制 (ACE)相比之下，抑制对慢性年龄相关损伤具有保护作用 与其他降压方案比较，并通过评价治疗效果 对血流动力学功能和损伤介质的研究；(3)检测 肾多巴胺能系统的活性及其与肾上腺皮质激素的相互作用 肾素-血管紧张素转换酶在调节老年人血流动力学和利钠功能中的作用 肾脏。结合使用生理、生化、 免疫组织化学和分子生物学方法应该获得洞察力 这个临床上重要但未被充分研究的问题。

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.