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D1-1 IKE受体在高血压中的功能障碍，但精确的D1样 涉及的受体仍有待确定。原因之一是缺乏D1样受体配体选择性 D1样受体亚型，D1R或D5R这一限制已被选择性克服 小鼠D1R和D5R基因的缺失：任何一种受体基因的破坏都会增加血压和 产生高血压。以前的资金期获得的数据表明D5 - / - 小鼠是高血压 部分原因是激活交感神经系统和增加的氧化应激。 多巴胺和血管紧张素II受体相互调节并相互作用以调节肾功能，但不是 已知D1样受体D1R或D5R调节AT1R作用。在肾近端小管细胞中，有75％ D1样受体功能由D1R提供，而仅25％是由于D5R引起的。但是，D1样受体 抑制肾脏Na+K+ATPase活性（部分被CAMP/PKA抑制）被废除并血液 尽管具有完整的D1R基因，但在D5 - / - 小鼠中的压力增加。因为肾脏AT1R蛋白增加 在D5 - / - 小鼠中，D1R作用的损害可能是由于AT1R表达增加所致。这反过 盐敏感高血压。实际上，D5 - / - 的高血压因NACI摄入量增加而加剧 AT1R阻断使D5 - / - 小鼠的血压归一化。在肾脏近端小管细胞中，D5R，但不是D1R 降低AT1R蛋白，无法通过转录或翻译减少来解释。 D5R是 组成性泛素化和05R刺激增加了AT1R的泛素化。蛋白酶体的封锁 防止D5R介导的AT1R蛋白表达降低。这些数据在HEK-293中得到了证实 表达D5R和AT1R的细胞。因此，可能引起D5 - / - 小鼠中AT1R蛋白的增加可能 是由于D5R未能下调AT1的原因。假设D5R缺乏导致 AT1R表达，钠敏感性和高血压增加。特定目标1WILL检验假设 D5 - / - 小鼠中的高血压部分是由肾脏AT1R表达增加引起的。具体目标2将 测试假设D1样和AT1RS的反调节是由多种机制引起的 包括蛋白质/蛋白质相互作用和蛋白酶体降解。对机制的了解 当D5R功能受损时，高血压会发展出可能导致靶向疗法的发展。