D2 receptor variation and renal dysfunction

盐敏感（SS）个体摄入高Na+不仅会发生高血压， 损伤/慢性肾脏疾病（CKD）和心血管疾病（CVD）。减少Na+ 摄入可预防和治疗高血压、CVD和CKD。然而，低Na+摄入量可能不会 对高血压或心血管疾病的治疗总是有益的。低Na+摄入与 具有增加的高血压风险（即，逆盐敏感性（ISS），CVD和死亡。 高血压和糖尿病是肾损害的主要原因，占肾损害的75%。 终末期肾病然而，高血压可能仅在遗传上引起CKD。 易受影响在GEO数据集中的16项CKD患者研究中，13项研究中，多巴胺2型受体 (D2R)CKD患者的DRD 2基因表达低于非CKD患者。减少 在D2 R的表达或功能中，本身或由DRD 2变体引起， 炎症、肾纤维化和ISS。ISS的机制/遗传学尚未得到很好的理解。 具有Drd 2的全局生殖系缺失（Drd 2-/-）的小鼠具有SS高血压和ISS。然而，在这方面， 肾近曲小管（RPT）特异性条件性缺失Drd 2（Drd 2cPT）的小鼠， 只有当Na+摄入量减少时，血压（BP）才会升高，这是ISS的一例。斯普拉格- 道利大鼠患有ISS，与血管紧张素1型受体活性增加有关 （AT 1 R）和α1-肾上腺素能受体。大约15%的高血压患者患有ISS， 与DRD 2 rs6276/rs6277相关。DRD 2变体rs6277在小鼠肾脏中的选择性表达 小鼠血压升高，肾脏Na+转运和排泄抑制减弱。我们将测试 DRD 2/Drd 2在通过减轻过度 活性肾素-血管紧张素和交感神经系统以及RPT Na+增加 低钠饮食运输。具体目标1将检验在Drd 2-/-或Drd 2cPT中 在小鼠中，当Na+摄入量“低”时，血压会升高，这是ISS的一种情况。Drd 2-/-或 喂食低Na+饮食的Drd 2cPT小鼠是由RPT Na+转运的D2 R抑制受损引起的， RPT Na+转运的增加是由肾素-血管紧张素和 交感神经系统从长远来看，肾功能下降，因为 未减轻的肾纤维化。具体目标2将测试DRD 2变异的假设， rs6276/rs6277，降低依赖于转录作用的D2 R表达， 因子NR 4a 2和miR 4301。这些研究意义重大，因为它们可能 导致确定将受到当前气候变化不利影响的人口 建议减少每个人的Na+摄入量。

Salt-sensitive (SS) individuals on high Na+ intake not only develop hypertension but also kidney injury/ chronic kidney disease (CKD) and cardiovascular disease (CVD). A reduction in Na+ intake may prevent and treat hypertension, CVD, and CKD. However, low Na+ intake may not always be beneficial in the treatment of hypertension or CVD. A low Na+ intake is associated with increased risk of hypertension (i.e., inverse salt sensitivity (ISS), CVD, and death. Hypertension and diabetes are the major causes of renal injury, accounting for up to 75% of end-stage renal disease. However, hypertension may cause CKD only in the genetically susceptible. In 13 of 16 studies in the GEO Dataset of CKD patients, dopamine type 2 receptor (D2R) gene (DRD2) expression is lower in those with CKD than those without CKD. A decrease in the expression or function of D2R, per se, or caused by DRD2 variants, increases renal inflammation, renal fibrosis, and ISS. The mechanisms/genetics of ISS are not well understood. Mice with global germline deletion of Drd2 (Drd2-/-) have SS hypertension and ISS. However, mice with renal proximal tubule (RPT)-specific conditional deletion of Drd2 (Drd2cPT) have increased blood pressure (BP) only when Na+ intake is decreased, a case of ISS. Sprague- Dawley rats have ISS, related to an increase in the activity of the angiotensin type 1 receptor (AT1R) and α1-adrenoceptors. About 15% of hypertensive subjects have ISS and some associated with DRD2 rs6276/rs6277. Renal-selective expression of DRD2 variant rs6277 in mice should increase BP and impair inhibition of renal Na+ transport and excretion. We will test the overall hypothesis that DRD2/Drd2 is important in preventing ISS by mitigating overly active renin-angiotensin and sympathetic nervous systems and the increase in RPT Na+ transport on a low Na+ diet. Specific Aim 1 will test the hypothesis that in Drd2-/- or Drd2cPT mice, BP increases when Na+ intake is “low”, a case of ISS. The increase in BP in Drd2-/- or Drd2cPT mice fed a low Na+ diet is caused by impaired D2R inhibition of RPT Na+ transport and an increase in RPT Na+ transport caused by activation of both the renin-angioten-sin and sympathetic nervous systems. In the long-term, renal function is decreased because of unmitigated renal fibrosis. Specific Aim 2 will test the hypothesis that DRD2 variants, rs6276/rs6277, decrease D2R expression that is dependent on the effects of the transcription factors NR4a2 and miR4301. These studies are significant and important because they may lead to the identification of the human population that would be adversely affected by the current recommendation to decrease the Na+ intake in everyone.