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: 10339345
• 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 2024-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10339345
• 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 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; 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; blood pressure elevation; chemokine; chromatin immunoprecipitation; cytokine; diet-induced obesity; endothelial dysfunction; gene regulatory network; 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

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)在血管和肾脏的病理生理后果中的作用 系统和血管紧张素受体1型(AT1R)介导这些效应。AT1R-信令 促进肾钠滞留、血管重塑、高血压和终末器官损伤。 增加AT1R的基因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，基因可变的转录调控 对人类AT1R基因的研究还知之甚少。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。在这方面，人类 AT1R基因由4个SNPs组成：T/A-810、T/G-713、A/C-214和A/G 启动子AT-153。变体-810T、-713T、-214A和-153A总是同时出现 (单体型-I)和变异体-810A、-713G、-214C和-153G总是同时出现(单体型-II)。 我们已经发现单倍型-I与高加索人的高血压有关，并且 构建hAT1R基因单倍型-I和II的转基因小鼠以研究其转录 监管。单倍型-I的TG小鼠hAT1R表达增加，血液增加 压力；抑制抗氧化防御(HO1，SOD1)和抗衰老分子(ATRAP， 炎症(IL-6、肿瘤坏死因子、C反应蛋白、IL-1β)和氧化的表达增加 标记(NOX1)。另一方面，饮食诱导的肥胖和衰老也伴随着 全身性炎症和氧化还原失衡，进而改变细胞转录环境。 我们的初步研究表明，USF2、GR等转录因子具有较高的结合亲和力 与单倍型相比，STAT3可增加单倍型-I转基因小鼠hAT1R的表达。 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翻译价值和重要的临床意义。 因此，在这个应用中，我们将分析饮食和年龄是如何影响细胞基因调控的 并改变我们转基因系中hAT1R的表达。为了消除混乱 内源性mAT1R基因的影响，mA1TR-/-hAT1R-TG小鼠将被使用。因此， 了解不同生理变量如年龄或饮食在AT1R基因调控中的作用 对于识别反馈AT1R过度表达风险增加的患者至关重要。这可以起作用 作为对慢性阻塞性肺疾病患者进行及时和定向治疗干预的早期预警 AT1R基因单倍型-I。