Renin cell identity and blood pressure homeostasis

肾素细胞特性和血压稳态

• 批准号: 10398851
• 负责人: MARIA LUISA Soledad SEQUEIRA-LOPEZ
• 金额: $ 69.05万
• 依托单位: UNIVERSITY OF VIRGINIA
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-01 至 2024-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10398851
• 关键词: Adoption; Adult; Aortic coarctation; Architecture; Biological; Biological Availability; Blood Pressure; Blood Vessels; Cardiovascular Diseases; Cell Lineage; Cell Nucleus; Cells; Child; Chromatin; Chronic; Cytoplasm; DNA; Dehydration; Disease; Drops; Enhancers; Equilibrium; Event; F-Actin; Fibronectins; Gene Expression; Genes; Genetic Transcription; Health; Heart failure; Histones; Homeostasis; Hypertension; Image; In Vitro; Integrins; Juxtaglomerular Cell; Kidney; Kidney Diseases; Knowledge; Label; Laboratories; Lamin Type A; Lead; Location; Mechanics; Medical; Memory; Modeling; Molecular; Molecular Conformation; Movement; Mus; Nature; Nuclear; Nuclear Envelope; Perfusion; Phenotype; Pressoreceptors; Prevention; Process; Regulation; Renal Hypertension; Renin; Renin-Angiotensin System; Research; Smooth Muscle Myocytes; Structure; Testing; Transcriptional Regulation; Variant; Vascular Diseases; Vascular Smooth Muscle; Visualization; Work; arteriole; blood pressure control; blood pressure regulation; burden of illness; chromatin remodeling; conditional knockout; epigenomics; experimental study; extracellular; in vivo; inhibitor; magnetic beads; mechanical force; mechanical pressure; mechanical signal; mechanical stimulus; mechanotransduction; operation; preservation; pressure; renal artery; response

PROJECT SUMMARY/ABSTRACT The renin-angiotensin system (RAS) is crucial in the regulation of the blood pressure (BP). Synthesis and secretion of renin is the key regulated event in the operation of the RAS. One of the main mechanisms that control renin synthesis and release is the baroreceptor mechanism whereby a decrease in BP results in increased release of renin by juxtaglomerular (JG) cells. Under normal circumstances, secretion of renin by JG cells is sufficient to balance transient changes in BP. However, if the drop in renal perfusion pressure is protracted, additional cells along the renal arterioles are transformed to the renin phenotype to meet the perceived demands for renin and regain homeostasis. In spite of its enormous importance, the nature and location of the renal baroreceptor, and whether mechanical signals are transmitted directly to the renin cell nucleus to activate Renin gene expression is still unknown. It has been assumed that this pressure sensing mechanism is located at the afferent arterioles either in the JG cells or the vascular smooth muscle cells (SMCs) upstream from them. Recent studies from our laboratory identified a unique set of super-enhancers (SEs) that determine the identity of renin cells, in which the Renin SE ranked the highest. External mechanical forces may trigger changes in nuclear envelope structure, chromatin organization and gene expression. We hypothesize that JG cells and/or their descendants sense variations in perfusion pressure and respond to them with marked and unique changes in chromatin configuration resulting in changes in Renin gene expression and in the case of SMCs the adoption of the renin phenotype via the assembly of a Renin SE. We further hypothesize that this pressure sensing mechanism is a nuclear mechanotransduction process whereby extracellular physical forces are transmitted directly to the chromatin to regulate Renin gene expression, renin bioavailability and cell identity. Whether the same set of SEs or a different set is activated in response to changes in perfusion pressure is unknown. Using multiple approaches, well established in our laboratories, including genetically modified mice, cell lineage tracing, in vivo high and low perfusion pressure models, epigenomic analysis and editing, and in vitro imaging of chromatin dynamics, we will test the following hypotheses: Aim 1: Changes in perfusion pressure sensed by renin cells and/or their descendants result in unique and specific changes in chromatin architecture which in turn control the expression of Renin and the identity of renin cells, Aim 2: Integrin β1 controls renin cell identity via chromatin architectural changes and SE formation, and Aim 3: Lamin A/C regulates chromatin remodeling and the formation of SEs in renin cells in response to changes in arterial pressure in vivo and mechanical deformation in vitro. This research is crucial to understand how BP homeostasis is maintained in health and disease. Knowledge gained from the proposed work may open new research avenues and be of help in the prevention and treatment of adults and children suffering from cardiovascular diseases and hypertension.

项目总结/摘要 肾素-血管紧张素系统（RAS）在血压调节中起着重要作用。合成与 肾素的分泌是RAS运作中的关键调节事件。其中一个主要的机制， 控制肾素合成和释放是压力感受器机制，由此血压降低导致 肾小球（JG）细胞释放的肾素增加。正常情况下，JG分泌的肾素 细胞足以平衡血压的瞬时变化。然而，如果肾灌注压下降， 沿着肾小动脉的延长的额外细胞沿着被转化为肾素表型，以满足 感知对肾素的需求并恢复体内平衡。尽管它的重要性，性质和 肾压力感受器的位置，以及机械信号是否直接传递到肾素细胞 细胞核激活肾素基因表达仍然是未知的。已经假设这种压力感测 其机制位于JG细胞或血管平滑肌细胞（SMC）的传入小动脉 从他们的上游。我们实验室最近的研究确定了一组独特的超级增强子（SE）， 确定其中Renin SE排名最高的Renin细胞的身份。外部机械力可以 引发核膜结构、染色质组织和基因表达的变化。我们假设 JG细胞和/或其后代感知灌注压的变化，并以显著的 染色质构型的独特变化导致肾素基因表达的变化， 平滑肌细胞通过组装肾素SE而采用肾素表型。我们进一步假设， 压力感受机制是一种细胞外物理力 直接传递到染色质，以调节肾素基因表达、肾素生物利用度和细胞特性。 是否响应于灌注压的变化而激活相同的SE组或不同的SE组， 未知使用多种方法，在我们的实验室中建立良好，包括转基因小鼠， 细胞谱系追踪，体内高和低灌注压模型，表观基因组分析和编辑，以及体外 染色质动力学成像，我们将测试以下假设：目的1：灌注压的变化 由肾素细胞和/或它们的后代感知，导致染色质结构的独特和特异性变化 目的2：整合素β1调控肾素细胞的功能 目的3：核纤层蛋白A/C调节染色质 在体内响应动脉压变化的肾素细胞中重塑和SE的形成， 体外机械变形。这项研究对于了解血压稳态是如何维持的至关重要， 健康和疾病。从拟议的工作中获得的知识可能会开辟新的研究途径，并有所帮助 预防和治疗成人和儿童心血管疾病和高血压。