D2 receptor variation and renal dysfunction

D2受体变异与肾功能障碍

• 批准号: 10564943
• 负责人: Pedro A. Jose
• 金额: $ 70.6万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-01-20 至 2027-12-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10564943
• 关键词: Accounting; Adrenergic Receptor; Affect; Age; Aldosterone; Amish; Angiotensins; Animal Model; Blood Pressure; Cardiovascular Diseases; Catecholamines; Cells; Cessation of life; Chinese population; Chronic Kidney Failure; Collection; Consumption; Data Set; Diabetes Mellitus; Diastolic blood pressure; Diet; Dietary Assessment; Dopamine; Dopamine D2 Receptor; Double-Blind Method; End stage renal failure; Epigenetic Process; Essential Hypertension; Etiology; Excretory function; Failure; Gene Expression; Genes; Genetic; Human; Hypertension; Impairment; Incidence; Individual; Inflammation; Injury to Kidney; Insulin Resistance; Intake; Kidney; Kidney Diseases; Lipids; Lipoproteins; Mediating; Mus; NR4A2 gene; National Health and Nutrition Examination Survey; Non obese; Patients; Plasma; Population; Predisposition; Prevalence; Proximal Kidney Tubules; Randomized; Receptor Gene; Receptor Inhibition; Receptor, Angiotensin, Type 1; Recommendation; Renal function; Renal tubule structure; Renin; Renin-Angiotensin System; Research; Reservations; Resistance; Risk; Role; Sodium Chloride; Sprague-Dawley Rats; Surveys; Sympathetic Nervous System; Testing; Urine; Variant; Vascular Diseases; blood pressure elevation; cardiovascular disorder risk; cardiovascular risk factor; comorbidity; genetic variant; human old age (65+); hypertension treatment; hypertensive; inflammatory marker; kidney dysfunction; kidney fibrosis; mortality; normotensive; obese person; precision medicine; premature; pressure; prevent; receptor; receptor expression; receptor function; salt intake; salt sensitive; selective expression; transcription factor; urinary

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.

盐敏感(SS)人群摄入高Na+不仅会患高血压，还会患上肾脏 损伤/慢性肾脏疾病(CKD)和心血管疾病(CVD)。钠离子的减少 摄入可以预防和治疗高血压、心血管疾病和慢性肾脏病。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+摄入量与 高血压(即逆盐敏感性(ISS)、心血管疾病和死亡)风险增加。 高血压和糖尿病是肾损伤的主要原因，占高达75% 终末期肾病。然而，高血压可能只在遗传上引起CKD。 易受影响。在CKD患者GEO数据集的16项研究中，有13项是多巴胺2型受体 CKD患者的D2R基因(DRD2)表达低于无CKD患者。减少 在D2R的表达或功能上，本身或由DRD2变体引起的，增加肾脏 炎症、肾纤维化和ISS。国际空间站的机制/遗传学还不是很清楚。 具有Drd2(drd2-/-)整体胚系缺失的小鼠患有SS高血压和ISS。然而， 具有肾近端小管(RPT)特异性Drd2条件性缺失(Drd2cPT)的小鼠 只有当钠离子摄入量减少时，血压才会升高，这是ISS的一个例子。斯普拉格- Dawley大鼠有ISS，与血管紧张素1型受体活性增加有关 (AT1R)和α1-肾上腺素能受体。大约15%的高血压患者有ISS和一些 与DRD2 rs6276/rs6277相关联。DRD2突变体rs6277的肾脏选择性表达 小鼠应升高血压，减轻对肾脏Na+转运和排泄的抑制。我们将测试 总体假设认为DRD2/DRD2通过减轻过度的 活性肾素-血管紧张素和交感神经系统与RPT、Na+的升高 低钠饮食下的运输。特定目标1将检验假设，在Drd2-/-或Drd2cPT中 小鼠，当钠离子摄入量“低”时，血压会升高，这是ISS的一个例子。DRD2-/-或血压升高 喂食低钠饮食的Drd2cPT小鼠是由于D2R抑制RPT Na+转运和 肾素-血管紧张素和血管紧张素转换酶激活引起的RPT钠离子转运增加 交感神经系统。从长远来看，肾功能下降是因为 未减轻的肾脏纤维化。《特定目标2》将测试DRD2变种， Rs6276/rs6277，降低D2R的表达，这依赖于转录的影响 因子NR4a2和miR4301。这些研究意义重大，因为它们可能 导致查明将受到当前危机不利影响的人口 建议减少每个人的Na+摄入量。