Project #1: Chronic stimulation of renin cells and transformation of the kidney vasculature

项目概要/摘要 肾小球旁（JG）细胞是传感器，在整个进化过程中完善，以解释和响应细胞内的变化。 血压和细胞外液的组成和体积。正常情况下，JG细胞释放的肾素 足以维持体内平衡。然而，在强烈和长期的生理挑战（脱水， 钠耗竭、低血压）沿着肾小动脉的平滑肌细胞（SMC）沿着重新获得肾素 表型和恢复稳态。一旦体内平衡重新建立，转化的细胞就停止制造 再变成平滑肌细胞。相反，如果煽动性威胁没有消除或克服[如在自发 或小鼠中的肾素-血管紧张素系统（RAS）基因的实验性突变或RAS的慢性抑制， 大鼠和人类]持续的慢性刺激肾素细胞导致肾内向心性肥大， 动脉和小动脉。大量肥大的肾素细胞包围着小动脉，并混乱地插入其中。 墙SMC同心地向内积聚，使血管腔变窄并限制血流， 导致局部缺血、纤维化和肾衰竭。尽管它在医学上的重要性，以及RAS的普遍使用 抑制剂在儿童和青少年，这种严重的，虽然沉默， 疾病未知。我们的肾素细胞消融研究表明， 疾病不仅通过物理参与增厚的血管壁，而且还通过他们的直接细胞对细胞 与SMC的互动。我们实验室的大量初步数据表明，cAMP和Notch 这些通路负责肾素细胞的转化和动脉疾病。我们假设 在慢性无限制的刺激下，p300重塑了肾素细胞的染色质，使它们成为一个双重的 胚胎衰老表型此外，转化的肾素细胞，通过Notch激活诱导向心性细胞凋亡。 邻近SMC的血管肥大。目的1将检验特异性印迹染色质 结构域决定了负责向心性动脉肥大的细胞命运的进行性变化。目的 图1A将确定组成患病小动脉的细胞的身份和命运。目标1B将测试是否 源自患病小动脉的细胞保持在（或恢复到）胚胎/祖细胞状态。目的2 将测试组蛋白乙酰转移酶p300负责这些染色质的产生的假设 决定肾素细胞的病理转化和向心性动脉肥大的结构域。 目的3将检验相邻SMC的同心聚集是由Notch信号介导的假设 通过肾素细胞中的Jagged1配体与SMC中的Notch2受体的结合。使用新颖 概念和技术的方法，拟议的工作将揭示的基本机制，染色质 结构域和转录驱动程序负责细胞命运的变化，导致这种严重的动脉疾病。 这项工作有可能为合理鉴定靶点开辟新的转化机会， 设计保护患有肾脏疾病和高血压的儿童和成人肾脏的特殊疗法。

PROJECT SUMMARY/ABSTRACT Juxtaglomerular (JG) cells are sensors, perfected throughout evolution to interpret and respond to changes in blood pressure and the composition and volume of the extracellular fluid. Normally, renin release from JG cells suffice to maintain homeostasis. However, under intense and prolonged physiological challenges (dehydration, sodium depletion, hypotension) smooth muscle cells (SMCs) along the kidney arterioles reacquire the renin phenotype and restore homeostasis. Once homeostasis is reestablished, the transformed cells stop making renin and become SMCs again. Conversely, if the inciting threat is not removed or overcome [as in spontaneous or experimental mutations of the renin-angiotensin system (RAS) genes or chronic inhibition of the RAS in mice, rats and humans] the relentless chronic stimulation of renin cells leads to the concentric hypertrophy of intrarenal arteries and arterioles. Numerous hypertrophic renin cells surround -and insert chaotically within- the arteriolar walls. SMCs accumulate concentrically and inwardly, narrowing the vessel lumens and restricting blood flow, resulting in ischemia, fibrosis and renal failure. In spite of its medical importance, and the prevalent use of RAS inhibitors in children and adolescents, the mechanisms underlying the development of this severe, albeit silent, disease are not known. Our renin cell ablation studies indicated that renin cells are responsible for the vascular disease not only by physically participating in the thickening of the vessel wall but also by their direct cell-to-cell interaction with SMCs. Abundant preliminary data from our laboratory suggest that the cAMP and Notch pathways are responsible for the transformation of renin cells and the arterial disease. We hypothesize that under chronic unrestrained stimulation, p300 remodels the chromatin of renin cells leading them to a dual embryonic-senescent phenotype. Further, the transformed renin cells, via Notch activation induce the concentric vascular hypertrophy of the adjacent SMCs. Aim 1 will test the hypothesis that specific imprinted chromatin domains determine the progressive changes in cell fate responsible for the concentric arterial hypertrophy. Aim 1A will define the identity and fate of the cells that compose the diseased arterioles. Aim 1B will test whether cells derived from the diseased arterioles are retained in (or reverted to) an embryonic/progenitor state. Aim 2 will test the hypothesis that Histone acetyltransferase p300 is responsible for the generation of those chromatin domains that determine the pathological transformation of renin cells and the concentric arterial hypertrophy. Aim 3 will test the hypothesis that the concentric accumulation of adjacent SMCs is mediated by Notch signaling via the engagement of the Jagged1 ligand in renin cells with the Notch2 receptor in SMCs. Using novel conceptual and technical approaches, the proposed work will uncover the fundamental mechanisms, chromatin domains and transcriptional drivers responsible for the changes in cell fate leading to this severe arterial disease. The work has the potential to open new translational opportunities for the rational identification of targets for the design of specific therapies that protect the kidneys of children and adults with kidney diseases and hypertension.