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

项目摘要/摘要 肾小球旁(JG)细胞是感受器，在整个进化过程中不断完善，以解释和响应 血压和细胞外液的成分和体积。正常情况下，JG细胞释放肾素 足以维持动态平衡。然而，在激烈和长期的生理挑战下(脱水， 钠耗竭、低血压)沿肾小动脉的平滑肌细胞(SMC)重新获得肾素 表型和恢复动态平衡。一旦动态平衡重新建立，转化的细胞就停止制造 肾素，再次成为SMC。相反，如果煽动威胁不被消除或克服[如自发的 或肾素-血管紧张素系统(RAS)基因的实验性突变或对RAS的慢性抑制， [大鼠和人]肾素细胞的持续慢性刺激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小动脉，并杂乱无章地插入小动脉内 墙壁。SMC向内和向内聚集，使血管管腔变窄，限制血流， 导致缺血、纤维化和肾功能衰竭。尽管它在医学上很重要，而且RAS的普遍使用 儿童和青少年中的抑制物，这种严重的，尽管是沉默的， 疾病是未知的。我们的肾素细胞消融研究表明，肾素细胞负责血管 疾病不仅通过身体上参与血管壁的增厚，而且通过其直接的细胞到细胞 与SMCS的互动。来自我们实验室的大量初步数据表明，坎普和诺奇 途径是肾素细胞转化和动脉疾病的罪魁祸首。我们假设 在慢性无限制的刺激下，p300重塑肾素细胞的染色质，导致它们进入双重 胚胎衰老表型。此外，转化的肾素细胞通过Notch激活诱导同心 邻近SMC的血管肥厚。目标1将检验特定印迹染色质的假设 结构域决定了导致同心性动脉肥大的细胞命运的进行性变化。目标 1A将定义构成病变小动脉的细胞的身份和命运。Aim 1B将测试 来自病变小动脉的细胞保持(或恢复到)胚胎/祖细胞状态。目标2 将验证组蛋白乙酰转移酶p300负责产生这些染色质的假设 决定肾素细胞病理转化和同心性动脉肥厚的结构域。 目标3将验证相邻SMC的同心性聚集是由Notch信号介导的假设 通过肾素细胞的Jagged1配体与SMC的Notch2受体的结合。使用小说 概念和技术方法，拟议的工作将揭示基本机制，染色质 导致这种严重动脉疾病的细胞命运变化的结构域和转录驱动因素。 这项工作有可能为合理确定目标开辟新的翻译机会 设计专门的治疗方法，保护患有肾脏疾病和高血压的儿童和成人的肾脏。

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.