Dopamine-1 Receptor Defect in Hypertension

有大量证据表明，高血压患者的D_1-1IKE受体功能障碍，但精确的D_1样受体 涉及的受体仍有待确定。一个原因是缺乏D1样受体配体选择性地 D1R或D5R这一限制已被选择性地 小鼠D1R和D5R基因缺失：任一受体基因的破坏会增加血压和 会产生高血压。在之前的资助期获得的数据显示，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，但它不是 已知哪种D1R或D5R样受体调节AT1R的作用。在肾近端小管细胞中，75% D1R具有D1R样受体功能，而D5R仅提供25%的D1R功能。然而，D1样受体 取消对肾脏Na+-K+-ATPase活性的抑制(部分被cAMP/PKA抑制)和血液 尽管有完整的D1R基因，D5-/-小鼠的血压仍会增加。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。这又会导致 盐敏感型高血压。事实上，D5-/-的高血压由于Naci摄入量的增加和 AT1R阻断可使D5-/-小鼠血压恢复正常。在肾近端小管细胞中，D5R，而不是D1R 减少AT1R蛋白，这不能用转录或翻译减少来解释。D5R是 结构性泛素化和05R刺激增加AT1R的泛素化。蛋白酶体的阻断 阻止D5R介导的AT1R蛋白表达下降。这些数据在HEK-293中得到了证实 表达D5R和AT1R的细胞。因此，D5-/-小鼠AT1R蛋白的增加可能是 是由于D5R未能下调AT1R所致。据推测，D5R缺乏导致 AT1R表达增加，钠敏感性和高血压。具体目标1将检验这一假设 D5-/-小鼠的高血压在一定程度上是由肾脏AT1R表达增加引起的。特定目标2将 检验D1样和AT1Rs的逆调节是由几种机制引起的假设 包括蛋白质/蛋白质相互作用和蛋白酶体降解。对其机制的了解 当D5R功能受损时，就会发生高血压，这可能会导致靶向治疗的发展。

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.