Salt and Water Transporter Expression in Aging Kidneys

随着年龄的增长，肾脏浓缩能力逐渐丧失。老年患者的急性疾病通常因体液和电解质平衡紊乱而复杂化，这不仅费用昂贵，而且不方便，而且往往会延迟康复并延长住院时间。这项提议的长期目标是更好地了解完整衰老肾脏中盐和水平衡的过程。四种水通道（水通道蛋白；AQP-1至4），四种尿素转运蛋白异构体（UT-A1至4）和几种主要的钠转运蛋白在肾元和直血管中被表征，它们对肾脏调节盐和水平衡以及尿浓缩过程至关重要。人们普遍认为，抗利尿素调节的水通道AQP-2丰度的减少有助于利尿，这与衰老有关。在这些研究中需要验证的中心假设是，钠、尿素和水的重吸收减少，独立于抗利尿素和AQP-2丰度，也有助于这种水分流失。我们的基本原理是，检查这些蛋白质的表达水平、细胞内分布和随年龄增长的调节，将为这种情况的生理学和病理生理学提供额外的分子理解，并导致老年人医疗保健的改善。为了验证这一假设，我们提出了以下2个具体目的：1)确定年轻（3个月），中年（12个月）和老年（24个月）F344XBNFI大鼠肾细胞中近端小管和下降细肢水通道蛋白-1，收集尘水通道蛋白-2，-3和-4，四种已知的髓质uta区域亚型和主要钠通道的丰度和细胞内分布。F344XBNFI是美国国家衰老研究所（NIA）认可的肾脏衰老研究模型。2)中老年F344xBNF1 （f3440）大鼠血浆抗利尿激素（ADH）和醛固酮水平与转运蛋白和通道蛋白丰度及细胞内差异的相关性。这些研究很重要，因为它们将确定目标转运蛋白和激素关系，为未来深入研究这一老年人主要疾病的机制提供依据。

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.