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后果系统和血管紧张素受体1型（AT1R）介导了这些作用。 AT1R信号促进肾脏钠保留率，血管重塑，高血压和最终器官损伤。增加AT1R的遗传变异会导致与肾素相关的病理结局血管紧张素系统（RAS）过度活跃。但是，一般可变的转录调节人类AT1R基因的理解很少。年龄和饮食等生理变量改变了细胞的转录环境，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 AT -810，T/G AT -713，A/C AT -214和A/G 在其发起人中为-153。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与高加索人的高血压有关，并且用HAT1R基因的单倍型I和II产生的转基因小鼠研究其转录规定。具有单倍型-I的TG小鼠的HAT1R表达更高，血液增加压力;抑制抗氧化剂防御剂（HO1，SOD1）和抗衰老分子（Attrap，Attrap， Klotho，Sirt3）;并增加炎症（IL-6，TNF，CRP，IL-1β）和氧化的表达增加标记（NOX1）。另一方面，饮食引起的肥胖和衰老也伴随着全身性炎症和氧化还原不平衡反过来改变了细胞转录环境。我们的初步研究表明，诸如USF2，GR等转录因子的结合亲密关系较高与单倍型相比 ii。由于AT1R上调可能会恶化年龄和饮食的病理结局，因此了解其基因调节具有很高的翻译价值，并具有重大的临床影响。在此应用中，我们将分析饮食和年龄如何影响细胞基因调节网络并改变了我们的转基因线中的HAT1R表达。消除混杂内源性MAT1R基因，MA1TR - / - HAT1R-TG小鼠的作用。那，了解不同物理变量（如年龄或饮食）对AT1R基因调节的作用对于识别有反馈AT1R过表达风险增加的患者至关重要。这可以起作用作为对及时和指导治疗干预的“预警” AT1R基因的单倍型-I。