Salt and Water Transporter Expression in Aging Kidneys

衰老肾脏中盐和水转运蛋白的表达

• 批准号: 6439853
• 负责人: JAMES M TERRIS
• 金额: $ 7.41万
• 依托单位: HENRY M. JACKSON FDN FOR THE ADV MIL/MED
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-04-01 至 2004-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6439853
• 关键词: age difference; aging; aldosterone; animal old age; densitometry; diuresis; electrolyte balance; gene expression; immunocytochemistry; intracellular; juvenile animal; kidney; laboratory rat; mature animal; membrane transport proteins; protein isoforms; protein localization; proteomics; renal tubule; salts; sodium; urea; vasopressins; water channel; western blottings

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.

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会因液体和电解质平衡紊乱而变得复杂，这种情况不仅昂贵、不方便，而且常常会延迟康复并延长住院时间。该提案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。肾单位和直肠血管中有四种水通道（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，这些蛋白对于肾脏调节盐水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 丰度的减少会导致随着衰老而出现的利尿现象。这些研究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 丰度无关）也会导致水分流失。我们的理由是，随着年龄的增长，检查这些蛋白质的表达水平、细胞内分布和调节将为这种疾病的生理学和病理生理学提供额外的分子理解，并改善老年人的医疗保健。为了检验这一假设，我们提出以下 2 个具体目标： 1) 确定近端小管和降细肢水通道蛋白-1 的丰度和细胞内分布，收集灰尘水通道蛋白-2、-3 和 -4、四种已知的髓质 UT-A 区域亚型以及青年（3 个月）、中年（12 个月）和老年人（24 个月）肾单位中的主要钠通道 F344XBNFI 大鼠是国家衰老研究所 (NIA) 认可的肾脏衰老研究模型。 2) 将年轻、中年和老年 F344xBNF1 (F344BN) 大鼠血浆中加压素 (ADH) 和醛固酮水平与转运蛋白和通道蛋白丰度以及细胞内差异相关。这些研究很重要，因为它们将确定目标转运蛋白和激素关系，以便将来对这种主要的老年人疾病进行深入的机制研究。