Etiology of Age-Related Defects in Urine Concentration

在人类和动物中，肾脏响应生理需求而浓缩和稀释尿液的能力随着年龄的增长而下降。垂体激素精氨酸加压素（AVP）是肾脏水排泄的主要调节剂。AVP通过加压素激活G蛋白偶联的AVP V2受体（V2 R），调节膜插入和水通道（水通道蛋白-2（AP 2））的丰度，增加肾集合管的水渗透性。先前的研究表明，随着年龄的增长，AVP的分泌会增加而不是减少，这表明与年龄相关的尿液浓缩能力缺陷存在于肾脏中。我们推测，一个显着的贡献机制，年龄相关的损害，尿液浓缩和稀释是一个降低的肾脏反应循环AVP，随后降低的能力，以适应水平衡的变化。我们计划通过研究年轻（6个月）和老年（24个月）Fischer大鼠来验证这一假设，以确定肾脏AVP V2受体和AQP-2表达和功能的适应性变化是否在老年捕获到年轻大鼠中减少，这些大鼠受到一系列液体和电解质平衡的生理扰动。其中包括：1）减少细胞外液水分（脱水，目标1）; 2）增加细胞外液水分（水负荷，目标2）; 3）改变饮食钠摄入量（低、正常和高NaCl饮食，目标3）。在这些研究中，将使用新型碘化V2受体拮抗剂并通过北方分析来测量AVP V2受体表达。将通过Western和北方分析测量AQP 2表达。还将通过放射免疫测定法测量AVP分泌以与V2 R和AQP 2结果相关联。这些研究将通过确定从V2 R到AQP 2的途径的哪一部分可能是导致在大鼠中观察到的肾浓缩和稀释能力受损作为衰老的函数，来深入了解功能性肾衰老的分子机制。因此，这些结果，以及随后的未来研究从他们派生，应允许更好地理解的液体和电解质异常，所以经常看到在老年人，并导致一个更开明的方法来预防和治疗这些疾病。

The ability of the kidney to concentrate and dilute urine in response to physiological demands decreases with aging in both humans and animals. The pituitary hormone arginine vasopressin (AVP) is the major regulator of renal water excretion. AVP increases water permeability in the kidney collecting duct by regulating membrane insertion and abundance of the water channel, aquaporin-2 (AP2), via vasopressin activation of the G protein-coupled AVP V2 receptor (V2R). Previous studies have shown that AVP secretion is increased rather than decreased with aging, suggesting that the age-related defect in urinary concentrating ability resides in the kidney. We hypothesize that a significant contributing mechanism to age-related impairments in urine concentration and dilution is a decreased renal responsiveness to circulating AVP, with subsequent reduced ability to adapt to changes in water balance. We plan to test this hypothesis by studying young (6 month) and old (24 month) Fischer rats to determine if adaptive changes in renal AVP V2 receptor and AQP-2 expression and function are reduced in old captured to young rats subjected to a series of physiological perturbations of fluid and electrolyte balance. These include: 1) decreased extracellular fluid water (dehydration, Aim 1); 2) increased extracellular fluid water (water loading, Aim 2); and 3) altered dietary sodium intake (low, normal, and high NaCl diet, Aim 3). In these studies, AVP V2 receptor expression will be a measured using a novel iodinated V2 receptor antagonist and by Northern analysis. AQP2 expression will be measured by Western and Northern analysis. AVP secretion will also be measured by radioimmunoassay to correlate with the V2R and AQP2 results. These studies will provide insight into the molecular mechanisms underlying functional renal senescence by identifying which part of the pathway from V2R to AQP2 may be responsible for the observed impaired renal concentrating and diluting abilities observed in rats as a function of aging. These results, and the subsequent future studies deriving from them, should therefore allow a better understanding of the fluid and electrolyte abnormalities so frequently seen in elderly individuals, and lead to a more enlightened approach to prevention and therapy of these disorders.