Hypertension and inflammation: novel insights from human angiotensin type 1 receptor variants

高血压和炎症：人类血管紧张素 1 型受体变体的新见解

基本信息

批准号：
10090628
负责人：
Sudhir Jain
金额：
$ 41万
依托单位：
NEW YORK MEDICAL COLLEGE
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-04-01 至 2023-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10090628
关键词：
Adipose tissue Affect Affinity Age Aging Angiotensin I Angiotensin II Angiotensin II Type 1 Receptor Blockers Angiotensin Receptor Animals Antioxidants Aorta Attenuated Binding Biological Assay Biological Availability Blood Pressure Blood Vessels CREB1 gene Cardiovascular Diseases Caucasians Cell Adhesion Molecules Cells Chromatin Chronic Clinical Consequentialism Coupled Development Diet Disease Essential Hypertension Feedback Free Radicals Functional disorder GTP-Binding Protein alpha Subunits, Gs GTP-Binding Proteins Gender Gene Activation Gene Expression Gene Expression Regulation Generations Genes Genetic Transcription Genetic Variation Haplotypes Heart Heart failure Human Hypertension In Vitro Inflammation Inflammatory Interferon Type II Interleukin-1 beta Interleukin-6 Kidney Kidney Diseases Kidney Failure Losartan Mediating Membrane Messenger RNA Metabolic Diseases Mus Organ Outcome Oxidases Oxidation-Reduction Oxidative Stress Pathologic Pathology Patients Physiological Play Reactive Oxygen Species Receptor, Angiotensin, Type 1 Regulation Regulator Genes Renal Tissue Renal function Renin-Angiotensin System Reporter Research Support Risk Risk Factors Role SIRT1 gene STAT3 gene Signal Pathway Signal Transduction Sodium Stroke System TNF gene Testing Therapeutic Intervention Time Tissues Transcriptional Regulation Transfection Transgenic Mice Transgenic Organisms USF2 gene Up-Regulation Variant Vascular Diseases Vascular remodeling age effect aged anti aging chemokine chromatin immunoprecipitation cytokine diet-induced obesity endothelial dysfunction heme oxygenase-1 in vivo insight kidney vascular structure metabolic profile novel overexpression promoter receptor density response superoxide dismutase 1 systemic inflammatory response transcription factor western diet

项目摘要

Angiotensin II (Ang II) contributes to the pathophysiological consequences of vascular and renal systems and angiotensin receptor type 1 (AT1R) mediates these effects. AT1R-signaling promotes renal sodium retention, vascular remodeling, hypertension, and end organ damage. Genetic variations that increase AT1R can cause pathological outcomes associated with renin angiotensin system (RAS) over-activity. However, genetically variable, transcriptional regulation of the human AT1R gene is poorly understood. Physiological variables like age and diet alter the transcriptional milieu of cells and result in feedback activation of genes. In this regard, the human AT1R gene has a haplotype block of four SNPs: T/A at -810, T/G at -713, A/C at -214, and A/G at -153 in its promoter. Variants -810T, -713T, -214A, and -153A always occur together (haplotype-I) and variants -810A, -713G, -214C, and -153G always occur together (haplotype-II). We have found that haplotype-I is associated with hypertension in Caucasians, and have generated transgenic mice with haplotypes-I and II of the hAT1R gene to study its transcriptional regulation. TG mice with haplotype-I have higher expression of hAT1R with increased blood pressure; suppression of antioxidant defenses (HO1, SOD1) and antiaging molecules (ATRAP, Klotho, Sirt3); and, increased expression of inflammatory (IL-6, TNF, CRP, IL-1β) and oxidative markers (NOX1). On the other hand, diet-induced obesity and aging are also accompanied by systemic inflammation and redox imbalance that, in turn, alter the cellular transcriptional milieu. Our preliminary studies show that higher binding affinity of transcription factors like USF2, GR and STAT3 increase hAT1R expression in TG-mice with haplotype-I, as compared to haplotype- II. Since AT1R up-regulation can worsen the pathological outcomes of age and diet, understanding its gene- regulation has high translational value with significant clinical impact. Thus, in this application we will analyze how diet and age affect the cellular gene regulatory networks and alters hAT1R expression in our transgenic lines. To eliminate the confounding effects of the endogenous mAT1R gene, mA1TR-/--hAT1R-TG mice will be used. Thus, understanding the role of different physiological variables like age or diet on AT1R gene regulation is crucial to identify patients at increased risk of feedback AT1R overexpression. This can function as an “early warning” towards timely and directed therapeutic intervention in patients with haplotype-I of the AT1R gene.

血管紧张素 II (Ang II) 有助于血管和肾脏的病理生理学后果系统和 1 型血管紧张素受体 (AT1R) 介导这些效应。促进肾钠潴留、血管重塑、高血压和终末器官损伤。增加 AT1R 的遗传变异可导致与肾素相关的病理结果血管紧张素系统（RAS）过度活跃。人们对人类 AT1R 基因的了解知之甚少，年龄和饮食等生理变量会改变这一基因。细胞的转录环境并导致基因的反馈激活。在这方面，人类。 AT1R 基因具有四个 SNP 的单倍型块：T/A 位于 -810、T/G 位于 -713、A/C 位于 -214 和 A/G 在其启动子的 -153 处，变体 -810T、-713T、-214A 和 -153A 总是一起出现。（单倍型-I）和变体-810A、-713G、-214C 和-153G 总是一起出现（单倍型-II）。我们发现单倍型 I 与白种人的高血压有关，并且具有 hAT1R 基因单倍型 I 和 II 的转基因小鼠以研究其转录具有单倍型-I的TG小鼠具有较高的hAT1R表达并且血液增加。压力；抑制抗氧化防御（HO1、SOD1）和抗衰老分子（ATRAP、 Klotho、Sirt3)；以及炎症（IL-6、TNFα、CRP、IL-1β）和氧化的表达增加另一方面，饮食引起的肥胖和衰老也伴随着。全身炎症和氧化还原失衡反过来会改变细胞转录环境。我们的初步研究表明，USF2、GR 等转录因子具有更高的结合亲和力与单倍型-I相比，STAT3增加了具有单倍型-I的TG-小鼠的hAT1R表达 II. 由于 AT1R 上调会恶化年龄和饮食的病理结果，了解其基因调控具有很高的转化价值，具有重大的临床影响。因此，在本应用中，我们将分析饮食和年龄如何影响细胞基因调控网络并改变我们转基因品系中的 hAT1R 表达，以消除混杂因素。内源性 mAT1R 基因的影响，将使用 mA1TR-/--hAT1R-TG 小鼠。了解年龄或饮食等不同生理变量对 AT1R 基因调控的作用对于识别反馈 AT1R 过度表达风险增加的患者至关重要。作为对患有此类疾病的患者进行及时和定向治疗干预的“早期预警” AT1R 基因的单倍型-I。