Dopamine-1 Receptor Defect in Hypertension

高血压中的多巴胺-1 受体缺陷

• 批准号: 7921095
• 负责人: Pedro A. Jose
• 金额: $ 17.2万
• 依托单位: CHILDREN'S RESEARCH INSTITUTE
• 依托单位国家: 美国
• 财政年份: 2009
• 资助国家: 美国
• 起止时间: 2009-09-30 至 2011-09-29
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7921095
• 关键词: Acute; Agonist; Angiotensin II Receptor; Binding; Blood; Blood Pressure; Brain; Cells; Cholecystokinin; Clathrin; Clathrin-Coated Vesicles; Complement; Complex; Corpus striatum structure; Cyclic AMP; Cyclic AMP-Dependent Protein Kinases; Data; Defect; Development; Dopamine; Dopamine Receptor; Duct (organ) structure; Epithelial; Essential Hypertension; Excretory function; Extracellular Fluid; Failure; Figs - dietary; Functional disorder; Funding; G Protein-Coupled Receptor Genes; GTP-Binding Proteins; Gases; Genes; Genetic; Genetic Transcription; Genetic Variation; Human; Hypertension; Impairment; In Vitro; Inbred SHR Rats; Intake; Intestines; Kidney; Knowledge; Lead; Ligands; Limb structure; Link; Lysosomes; Mediating; Modeling; Modification; Mus; Na(+)-K(+)-Exchanging ATPase; Nephrons; Organ; Oxidative Stress; Parathyroid Hormones; Pathway interactions; Phenotype; Phospholipase; Phosphotransferases; Physiological; Production; Progress Reports; Protein Isoforms; Proteins; Proximal Kidney Tubules; Receptor Gene; Receptor Inhibition; Regulation; Renal function; Reporting; Research Personnel; Rodent; SRC gene; Second Messenger Systems; Small Intestines; Sodium; Sodium Chloride; Sympathetic Nervous System; System; Testing; Thick; Transgenic Mice; Translations; Ubiquitination; Vasoconstrictor Agents; Vasodilator Agents; adapter protein; arrestin 2; human PTH protein; in vivo; late endosome; multicatalytic endopeptidase complex; offspring; overexpression; pressure; prevent; programs; protein expression; protein protein interaction; receptor; receptor coupling; receptor function; salt sensitive; saluretic; second messenger; sorting nexin 1; therapeutic target; trafficking

There is substantial evidence for dysfunction of D1-1 ike receptors in hypertension but the precise D1-like receptor involved remains to be determined. One reason is the lack of D1-like receptor ligands selective to either of the D1-like receptor subtype, D1R or D5R This limitation has been overcome by the selective deletion of the D1R and D5R gene in mice: disruption of either receptor gene increases blood pressure and produces hypertension. Data obtained in previous funding period showed that D5-/- mice are hypertensive caused, in part, by activation of sympathetic nervous system and increased oxidative stress. Dopamine and angiotensin II receptors regulate each other and interact to regulate renal function but it is not known which D1-like receptor, D1R or D5R, regulates AT1R action. In renal proximal tubule cells, 75% of D1-like receptor function is afforded by D1R while only 25% is due to D5R. However, D1-like receptor inhibition of renal Na+K+ATPase activity (which is inhibited, in part, by cAMP/PKA) is abrogated and blood pressure is increased in D5-/- mice, in spite of an intact D1R gene. Because renal AT1R protein is increased in D5-/- mice, the impairment of D1R action may be due to increased AT1R expression. This in turn causes salt sensitive hypertension. Indeed, the hypertension of D5-/- is aggravated by increased NaCI intake and AT1R blockade normalizes blood pressure of D5-/- mice. In renal proximal tubule cells, D5R but not D1R decreases AT1R protein that cannot be explained by a decrease in transcription or translation. The D5R is constitutively ubiquitinated and 05R stimulation increases ubiquitination of AT1R. Blockade of proteasomes prevents the D5R-mediated decrease in AT1R protein expression. These data are corroborated in HEK-293 cells expressing D5R and AT1R. Therefore, the increase in AT1R protein in D5-/- mice may be caused may be caused by the failure of D5R to down-regulate AT1 R. It is hypothesized that D5R deficiency leads to increased AT1R expression, sodium sensitivity, and hypertension. Specific aim 1will test the hypothesis that hypertension in D5-/- mice is, in part, caused by increased renal AT1R expression. Specific aim 2 will test the hypothesis that the counter regulation of D1-like and AT1Rs are caused by several mechanisms including protein/protein interaction and proteasomal degradation. Knowledge of the mechanisms bywhich hypertension develops when D5R function is impaired may lead to the development of targeted therapeutics.

有大量证据表明高血压中 D1-1 样受体功能障碍，但精确的 D1 样受体 所涉及的受体仍有待确定。原因之一是缺乏 D1 样受体配体的选择性 D1 样受体亚型 D1R 或 D5R 中的任一种 此限制已被选择性克服 小鼠中 D1R 和 D5R 基因的缺失：任一受体基因的破坏都会增加血压和血压 产生高血压。之前资助期间获得的数据显示 D5-/- 小鼠患有高血压 部分原因是交感神经系统的激活和氧化应激的增加。 多巴胺和血管紧张素II受体相互调节并相互作用来调节肾功能，但事实并非如此 已知哪种 D1 样受体 D1R 或 D5R 调节 AT1R 的作用。在肾近曲小管细胞中，75% D1 样受体功能由 D1R 提供，而只有 25% 是由 D5R 提供的。然而，D1 样受体 肾 Na+K+ATP 酶活性的抑制（部分被 cAMP/PKA 抑制）被消除，血液 尽管 D1R 基因完整，但 D5-/- 小鼠的压力仍增加。因为肾AT1R蛋白增加 在 D5-/- 小鼠中，D1R 作用受损可能是由于 AT1R 表达增加所致。这反过来又导致 盐敏感性高血压。事实上，D5-/- 的高血压会因 NaCl 摄入量的增加而加剧，并且 AT1R 阻断使 D5-/- 小鼠的血压正常化。在肾近曲小管细胞中，D5R 但不是 D1R AT1R 蛋白的减少不能用转录或翻译的减少来解释。 D5R 是 组成型泛素化和 05R 刺激会增加 AT1R 的泛素化。蛋白酶体的封锁 防止 D5R 介导的 AT1R 蛋白表达下降。这些数据在 HEK-293 中得到证实 表达 D5R 和 AT1R 的细胞。因此，D5-/-小鼠中AT1R蛋白的增加可能是由于 是由于 D5R 未能下调 AT1 R 引起的。假设 D5R 缺陷导致 AT1R 表达增加、钠敏感性增加和高血压增加。具体目标1将检验假设 D5-/- 小鼠的高血压部分是由肾 AT1R 表达增加引起的。具体目标2将 检验 D1 样和 AT1R 的反向调节是由多种机制引起的假设 包括蛋白质/蛋白质相互作用和蛋白酶体降解。了解其机制 当 D5R 功能受损时出现高血压可能会导致靶向治疗的发展。