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: 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
• 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

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）参与血管和肾脏疾病的病理生理后果， 血管紧张素受体1型（AT 1 R）介导这些作用。AT 1 R信号 促进肾钠潴留、血管重塑、高血压和终末器官损伤。 增加AT 1 R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 人类AT 1 R基因的研究知之甚少。年龄和饮食等生理变量会改变 在细胞的转录环境中，这一过程会导致基因的反馈激活。在这方面，人类 AT 1 R基因有4个单倍型区：-810的T/A，-713的T/G，-214的A/C， 在其启动子中为-153。变体-810 T、-713 T、-214 A和-153 A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与高加索人的高血压有关， 用hAT 1 R基因的单倍型I和II构建转基因小鼠，研究其转录水平。 调控具有单倍型-I的TG小鼠具有较高的hAT 1 R表达， 压力;抑制抗氧化防御（HO 1，SOD 1）和抗衰老分子（ATRAP， Klotho，Sirt 3）;以及，增加炎症（IL-6，TNF α，CRP，IL-1β）和氧化 标记物（NOX 1）。另一方面，饮食引起的肥胖和衰老也伴随着 系统性炎症和氧化还原失衡，这反过来又改变了细胞转录环境。 我们的初步研究表明，转录因子如USF 2、GR 和STAT 3增加hAT 1 R表达在TG-小鼠与单体型-I，相比， 二.由于AT 1 R上调可使年龄和饮食的病理结果恶化， 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，在本申请中，我们将分析饮食和年龄如何影响细胞基因调控， 在我们的转基因株系中网络和改变hAT 1 R表达。为了消除混淆 将使用内源性mAT 1 R基因mA 1 TR-/--hAT 1 R-TG小鼠。因此，在本发明中， 了解不同生理变量（如年龄或饮食）对AT 1 R基因调控的作用 对于识别反馈AT 1 R过表达风险增加的患者至关重要。这可以发挥作用 作为“早期预警”，对患有 AT 1 R基因的单倍型I。