Novel mechanisms of HDAC1 regulation of renal collecting duct function

HDAC1调节肾集合管功能的新机制

• 批准号: 8868322
• 负责人: Kelly Hyndman
• 金额: $ 15.19万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-01 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8868322
• 关键词: AVPR2 gene; Acetylation; Acute; Address; Adverse effects; Advisory Committees; Affect; Anti-Inflammatory Agents; Anti-inflammatory; Apical; Body Fluids; Body Water; Brattleboro Rats; Cardiovascular Diseases; Cells; Chronic; Complication; Data; Deacetylation; Dehydration; Development; Diet; Disease; Diuresis; Down-Regulation; Duct (organ) structure; Electrolytes; Enzymes; Epigenetic Process; Equilibrium; Excretory function; Figs - dietary; Fluid Balance; Functional disorder; Genetic Transcription; Goals; HDAC1 gene; Health; Histone Deacetylase; Histones; Homeostasis; Hydration status; Hyponatremia; In Vitro; Inappropriate ADH Syndrome; Infusion procedures; Kidney; Kidney Concentrating Ability; Kidney Diseases; Knockout Mice; Link; Liquid substance; Lysine; Mass Spectrum Analysis; Mediating; Mediator of activation protein; Mentors; Modeling; Modification; Mus; Nephrogenic Diabetes Insipidus; Nitric Oxide; Nitric Oxide Synthase Type I; Non-Histone Chromosomal Proteins; Pathway interactions; Pharmaceutical Preparations; Phosphorylation; Physiological Processes; Physiology; Polyuria; Post-Translational Regulation; Production; Property; Proteins; Rattus; Regulation; Regulatory Pathway; Reporting; Research; Risk Factors; Role; Signal Transduction; Site; Small Interfering RNA; Sodium Chloride; Surface; Syndrome; Testing; Therapeutic Uses; Transcriptional Regulation; Vasopressins; Water; Water consumption; antidiuresis; apical membrane; aquaporin-2; in vivo; inhibitor/antagonist; interest; interstitial; novel; programs; protein function; receptor; research study; trafficking; water channel

DESCRIPTION (provided by applicant): Water balance is maintained through the regulation of water reabsorption by the renal collecting duct (CD) via the vasopressin (AVP) regulated water channel aquaporin-2 (AQP2). Dysfunction in AQP2 leads to diseases such as nephrogenic diabetes insipidus (polyuria) or antidiuresis syndrome (water retention), and severe fluid retention is a common ailment in cardiovascular disease. Histone deacetylase enzymes (HDACs) remove acetyl groups from lysines of histones leading to epigenetic modification of gene transcription or non-histone proteins in a post-translational manner. There is growing interest in the therapeutic use of HDAC inhibitors in cardiovascular disease because of their anti- inflammatory properties. Interestingly, a reported side effect of HDAC inhibitor use is hyponatremia, suggesting these drugs affect fluid balance. Thus, it is imperative that we gain a better understanding of the role of HDACs in body fluid balance in order to avoid potentially dangerous side effects. Our compelling preliminary data support a novel role for HDAC1 regulation of diuresis by regulating transcription and deacetylation of proteins in the CD. Our central hypothesis is that during excess water consumption, HDAC1 mediates diuresis via regulation of AQP2 apical expression by directly deacetylating AQP2, indirectly by decreasing expression of the AVP subtype 2 receptor (V2R), and indirectly by increasing in nitric oxide synthase-1 (NOS1) derived nitric oxide (NO). The following hypotheses will be tested: 1) To test the hypothesis that water balance is maintained by changes in collecting duct AQP2 acetylation and apical surface expression; 2) To test the hypothesis that hydration promotes deacetylation of AQP2 and/or downregulation of the V2R receptor via HDAC1 in the CD, thus promoting diuresis; 3) To test the hypothesis that HDAC1-dependent increases in CD NO derived from NOS1 leads to decreases in AQP2 surface expression. With the help of mentor and advisory team, I will continue on the path towards my long term goal of developing a strong, independent, research program in the field of cardio/renal physiology with a focus on addressing novel mechanisms underlying cardio/renal diseases.

描述（由申请方提供）：通过加压素（AVP）调节水通道水通道蛋白-2（AQP 2）调节肾集合管（CD）的水重吸收来维持水平衡。AQP 2的功能障碍导致诸如肾源性尿崩症（多尿）或抗利尿综合征（水潴留）的疾病，并且严重的液体潴留是心血管疾病中的常见疾病。组蛋白脱乙酰基酶（HDAC）从组蛋白的赖氨酸去除乙酰基，导致基因转录或非组蛋白蛋白质以翻译后方式的表观遗传修饰。由于HDAC抑制剂的抗炎特性，其在心血管疾病中的治疗用途越来越受到关注。有趣的是，HDAC抑制剂使用的副作用是低钠血症，表明这些药物影响液体平衡。因此，我们必须更好地了解HDAC在体液平衡中的作用，以避免潜在的危险副作用。我们令人信服的初步数据支持HDAC 1通过调节CD中蛋白质的转录和脱乙酰化来调节利尿的新作用。我们的中心假设是，在过量的水消耗，HDAC 1介导利尿通过调节AQP 2的顶端表达，直接脱乙酰化AQP 2，间接减少AVP亚型2受体（V2 R）的表达，间接增加一氧化氮合酶-1（NOS 1）衍生的一氧化氮（NO）。将检验以下假设：1）检验水平衡通过集合管AQP 2乙酰化和顶面表达的变化来维持的假设; 2）检验水合作用通过CD中的HDAC 1促进AQP 2的脱乙酰化和/或V2 R受体的下调，从而促进利尿的假设; 3）验证HDAC 1依赖性增加来自NOS 1的CD NO导致AQP 2表面表达减少的假设。在导师和咨询团队的帮助下，我将继续朝着我的长期目标前进，即在心/肾生理学领域建立一个强大的，独立的研究项目，重点是解决心/肾疾病的新机制。