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）参与血管和肾脏的病理生理后果