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

• 批准号: 9884785
• 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
• 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/9884785
• 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; Obesity; 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; endothelial dysfunction; heme oxygenase-1; in vivo; insight; kidney vascular structure; metabolic profile; novel; overexpression; promoter; receptor density; response; superoxide dismutase 1; transcription factor; western diet

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) 介导这些作用。 AT1R-信号 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。然而，基因变异、转录调控 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 细胞的转录环境并导致基因的反馈激活。对此，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 在其启动子中为-153。变体 -810T、-713T、-214A 和 -153A 始终一起出现 （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 生成具有 hAT1R 基因单倍型 I 和 II 的转基因小鼠以研究其转录 规定。单倍型-I 的 TG 小鼠 hAT1R 表达较高，血液中 hAT1R 表达较高 压力;抑制抗氧化防御（HO1、SOD1）和抗衰老分子（ATRAP、 克洛托，西尔特3）；并且，炎症（IL-6、TNFα、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 二.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和重大的临床影响。 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。为了消除混杂 为了考虑内源性mAT1R基因的影响，将使用mA1TR-/--hAT1R-TG小鼠。因此， 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 AT1R 反馈过度表达风险增加的患者至关重要。这个可以发挥作用 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。