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.

高Na+摄入量的盐敏感（SS）个体不仅发育高血压，还会发育肾脏 损伤/慢性肾脏疾病（CKD）和心血管疾病（CVD）。 Na+的减少 摄入可能会预防和治疗高血压，CVD和CKD。但是，低Na+摄入量可能不会 总是有益于治疗高血压或CVD。低Na+摄入量相关 随着高血压的风险增加（即盐敏感性（ISS），CVD和死亡。 高血压和糖尿病是肾脏损伤的主要原因，占高达75％ 末期肾脏疾病。但是，高血压可能仅在基因上引起CKD 易受影响的。在CKD患者的GEO数据集中的16项研究中，有13个是多巴胺2型受体 （D2R）基因（DRD2）的CKD表达低于没有CKD的基因。减少 在D2R的表达或函数上，本身或由DRD2变体引起的，增加了肾脏 炎症，肾纤维化和ISS。 IS的机制/遗传学尚不清楚。 DRD2（DRD2 - / - ）具有全球种系缺失的小鼠具有SS高血压和ISS。然而， 肾近端小管（RPT） - 特定条件删除DRD2（DRD2CPT）的小鼠具有 仅当Na+摄入量减少时，血压（BP）升高，这是ISS的情况。 sprague- Dawley大鼠具有ISS，与血管紧张素1型接收器的活动增加有关 （AT1R）和α1-肾上腺素受体。大约15％的高血压受试者患有ISS和一些 与DRD2 RS6276/RS6277相关。 DRD2变体RS6277的肾脏选择性表达 小鼠应增加BP并损害肾脏Na+转运和排泄的抑制作用。我们将测试 DRD2/DRD2对于防止ISS的总体假设通过缓解过度来防止ISS很重要 主动肾素 - 血管紧张素和交感神经系统以及RPT Na+的增加 低Na+饮食运输。特定目标1将检验以下假设：在DRD2 - / - 或DRD2CPT中 当Na+摄入为“低”时，小鼠，BP会增加。 drd2 - / - 或 喂养低Na+饮食的DRD2CPT小鼠是由D2R抑制RPT Na+转运和 由肾素 - 血管葡萄糖和激活引起的RPT Na+转运增加的增加 交感神经系统。从长远来看，肾功能降低了 未固定的肾纤维化。特定的目标2将检验以下假设：DRD2变体， rs6276/rs6277，降低D2R表达，取决于转录的影响 因素NR4A2和MIR4301。这些研究很重要，而且很重要，因为它们可能 导致对人口的识别，这将受到当前的不利影响 建议减少每个人的Na+摄入量。