Renin cell identity and blood pressure homeostasis

项目摘要/摘要 肾素-血管紧张素系统(RAS)在血压调节中起着至关重要的作用。综合和 肾素的分泌是RAS运行中的关键调节事件。其中一个主要的机制是 控制肾素的合成和释放是压力感受器机制，通过这种机制，血压下降会导致 肾小球旁(JG)细胞肾素释放增加。在正常情况下，JG分泌肾素 细胞足以平衡血压的瞬时变化。然而，如果肾脏灌注压的下降是 沿肾小动脉延长的额外细胞转化为肾素表型，以满足 感受到对肾素的需求，并恢复动态平衡。尽管它具有巨大的重要性，但大自然和 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 核内激活肾素基因的表达尚不清楚。据推测，这种压力感应 机制位于JG细胞或血管平滑肌细胞(SMCs)的传入小动脉。 在他们的上游。我们实验室最近的研究发现了一组独特的超级增强剂(SE)， 确定肾素细胞的身份，其中肾素SE排名最高。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/或它们的后代感觉到灌流压力的变化并对它们做出显著的反应 染色质构型的独特变化导致肾素基因表达的变化，在这种情况下 在SMC中，通过组装肾素SE而采用肾素表型。我们进一步假设这一点 压力传感机制是一种核力学转导过程，细胞外的物理力 直接传递到染色质以调节肾素基因的表达、肾素的生物利用度和细胞特性。 是否响应于灌流压力的变化而激活相同组的SE或不同的组 未知。使用多种方法，包括转基因小鼠，我们的实验室已经很好地建立了这些方法， 细胞谱系追踪，体内高和低灌流压模型，表观基因组分析和编辑，以及体外 对于染色质动力学的成像，我们将检验以下假设：目的1：灌流压力的变化 肾素细胞和/或其后代的感知导致染色质结构的独特和特定的变化 它进而控制肾素的表达和肾素细胞的特性，目的2：整合素β1控制肾素细胞 通过染色质结构变化和SE形成的同一性，以及目标3：Lamin A/C调节染色质 肾素细胞对动脉压变化的重塑和SES的形成 体外机械变形。这项研究对于了解血压如何维持体内平衡至关重要。 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 用于预防和治疗患有心血管疾病和高血压的成人和儿童。

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.