Salt and Water Transporter Expression in Aging Kidneys

随着年龄的增长，肾脏的集中能力会逐渐丧失。老年患者的急性疾病通常会因液体和电解质平衡紊乱而变得复杂，这是昂贵、不便的，往往会推迟康复和延长住院时间。这项建议的长期目标是更好地了解完整老化肾脏的盐分和水分平衡过程。四种水通道(水通道；AQP-1至4)、四种尿素转运蛋白亚型(UT-A1至4)和几种主要的钠转运蛋白在肾单位和直肠血管中已被鉴定，它们对肾脏调节水盐平衡和尿液浓缩过程至关重要。人们普遍认为，加压素调节的水通道AQP-2丰度的减少有助于随着年龄的增长而出现利尿。在这些研究中要检验的中心假设是，钠、尿素和水的重吸收减少，与加压素和AQP-2的丰度无关，也是导致水分丢失的原因。我们的理论基础是，研究这些蛋白的表达水平、细胞内分布和随年龄变化的调节将提供对这种疾病的生理学和病理生理学的更多分子理解，并有助于改善老年人的医疗保健。为了验证这一假说，我们提出了以下两个特定目标：1)测定青年(3月龄)、中年(12月龄)和老年(24月龄)F344XBNFI大鼠肾近端小管和下行细肢水通道蛋白-1、收集尘埃水通道蛋白-2、-3和-4、四种已知的延髓UT-A区亚型和主要钠通道的丰度和细胞内分布。2)F344xBNF1(F344BN)大鼠血浆加压素(ADH)和醛固酮水平与转运体和通道蛋白丰度及细胞内差异相关。这些研究很重要，因为它们将确定目标转运体和激素关系，以便未来深入研究这种主要的老年人疾病的机制。

With aging there is a progressive loss of renal concentrating ability. Acute illness in geriatric patients is often complicated by derangements in fluid and electrolyte balance that are costly, inconvenient and often delay recovery and prolong hospitalization. The long-term goal of this proposal is to better understand the process of salt and water balance in the intact aging kidney. Four water channels (aquaporins; AQP-1 to 4), four urea transporter isoforms (UT-A1 to 4), and several major sodium transporter proteins have been characterized in the nephron and vasa recta that are critical for renal regulation of salt and water balance and the urinary concentrating process. It is generally accepted that a decrease in the abundance of the vasopressin regulated water channel, AQP-2, contributes to diuresis seen with aging. The central hypotheses to be tested in these studies is that a decreased reabsorption of sodium, urea and water, independent of vasopressin and AQP-2 abundance, also contribute to this water loss. Our rationale is that an examination of the expression levels, intracellular distribution and regulation of these proteins with age will provide additional molecular understanding of the physiology and pathophysiology of this condition and lead to improvements in health care of the aged. To test this hypothesis we propose the following 2 Specific Aims: 1) Determine the abundance and intracellular distribution of proximal tubule and descending thin limb aquaporins-1, collecting dust aquaporins-2, -3 and -4, the four known medullary UT-A area isoforms and the major sodium channels among the nephron in young (3 month), middle aged (12 months) and elderly (24 months) F344XBNFI rats, a National Institute of Aging (NIA) endorsed model for renal aging studies. 2) Correlate plasma levels of vasopressin (ADH) and aldosterone with differences in transporter and channel protein abundance and intracellular in young, middle-aged and elderly F344xBNF1 (F344BN) rats. These studies are important because they will identify target transporters and hormonal relationships for future in-depth mechanistic investigations of this major disorder of the aged.