Renal Pericytes as a Target for Angiotensin II Signaling in Hypertension

项目总结 肾素-血管紧张素系统(RAS)在调节全身血压中起着核心作用。如图所示 由于RAS靶向药物如血管紧张素受体阻滞剂的已被证实的益处，这些药物对 治疗高血压、心力衰竭和肾脏疾病。RAS的作用依赖于多肽 血管紧张素II(Ang II)作用于表达G蛋白偶联1型血管紧张素受体的细胞(人： AT1；鼠标：AT1a)。我们的小组一直站在揭示Ang II信号的细胞特定作用的前沿 在肾脏的不同细胞群中。这些研究揭示了Ang II扮演的新角色 在不同的细胞类型中驱动与高血压相关的发病机制。这表明， 总体而言，血管紧张素Ⅱ对血压的全身作用是血管紧张素Ⅱ在多个细胞上累积作用的结果。 正文中的类型。我们的初步研究分析了最近发表的单细胞RNA测序数据集 探讨血管紧张素受体在肾脏中的细胞特异性表达。我们发现周细胞，一幅壁画 与毛细血管和肾小球相关的细胞类型，表达小鼠AT1a受体。此外，我们 通过测量肾脏快速分离的周细胞的AT1a表达证实了这一点。然而，这个角色 血管紧张素信号在周细胞中的作用仍未得到充分研究。尽管有多条证据表明 提示肾周细胞在调节血压和肾损伤中起中心作用，与血管紧张素相关 在高血压和慢性肾脏疾病中病理改变的过程。该项目将测试 周细胞内血管紧张素II信号参与高血压发生的总体假说 和肾脏损伤。这位候选人开发了一种新的小鼠品系，它具有可诱导的周细胞特异性缺失 AT1a受体。首先，周细胞Ang II信号对血压控制的贡献将是 在基础状态下和Ang II高血压期间测定。接下来，血管紧张素转换酶II信号转导系统在 将评估高血压背景下肾周细胞的损伤情况。这项研究将由一个 受过良好的生物医学研究培训，并有良好的出版记录。为此而进行的训练 俄勒冈健康与科学大学肾脏病与高血压学部将提出一项提案 在苏珊·格利博士的主要指导下，苏珊·格利博士是RAS信号的细胞特异性行为领域的领先者 在肾脏里。该项目还将得到另外两位共同导师的支持：阿努莎·米什拉博士，一位 周细胞生物学和微血管血流，以及血管纤维化信号专家Lynne Sakai博士。 职业发展活动包括小鼠显微外科培训、体外切片成像、评估 肾脏病理学，以及单细胞RNA测序数据集的生物信息学分析。本培训旨在 推出下一代肾脏研究的候选人，拥有精湛的动物生理学技能 和分子生物学。这将为候选人满足他长期职业生涯成为一名 专注于高血压和肾脏损伤的细胞和分子原因的独立调查者。

PROJECT SUMMARY The renin-angiotensin-system (RAS) plays a central role in regulating systemic blood pressure. This is illustrated by the proven benefit of RAS-targeted drugs such as angiotensin receptor blockers, which are critical to the treatment of hypertension, heart failure and kidney disease. The actions of the RAS depend on the peptide angiotensin II (ang II) acting on cells that express the G-protein coupled type 1 angiotensin receptor (human: AT1; mouse: AT1a). Our group has been at the forefront of unmasking cell-specific roles of ang II signaling within different cell populations in the kidney. These studies have revealed novel roles for ang II to act distinctly in different cell types to drive pathogenic mechanisms associated with hypertension. This suggests that the overall, systemic effect of ang II on blood pressure results from the cumulative actions of ang II on multiple cell types within the body. Our preliminary studies analyzed recently published single-cell RNA Sequencing datasets to explore the cell-specific expression of angiotensin receptors within the kidney. We find that pericytes, a mural cell type associated with capillaries and the glomerulus, express the mouse AT1a receptor. Additionally, we confirmed this by measuring AT1a expression from rapidly sorted pericytes from the kidney. However, the role of angiotensin signaling in pericytes remains under-examined. This is despite multiple lines of evidence that suggest renal pericytes play a central role in regulating blood pressure and renal injury, angiotensin-linked processes which are pathologically altered in hypertension and chronic kidney disease. This project will test the overall hypothesis that angiotensin II signaling within pericytes contributes to the development of hypertension and renal injury. This candidate has developed a novel mouse line which has inducible pericyte-specific deletion of the AT1a receptor. First, the contribution of pericyte ang II signaling to blood pressure control will be determined under baseline conditions and during ang II hypertension. Next, the effect of ang II signaling within pericytes on renal injury in the context of hypertension will be assessed. This research will be carried out by an applicant with excellent training in biomedical research with a strong publication record. The training for this proposal will occur at Oregon Health & Science University within the Division of Nephrology and Hypertension under the primary mentorship of Dr. Susan Gurley a leader in the field of cell-specific actions of RAS signaling in the kidney. This project will also be supported by two other co-mentors: Dr. Anusha Mishra, an expert on pericyte biology and microvascular blood flow, and Dr. Lynne Sakai, an expert on vascular fibrotic signaling. Career development activities include training in mouse micro-surgery, ex vivo slice imaging, assessment of renal pathology, and bioinformatic analysis of single-cell RNA sequencing datasets. This training is designed to launch the candidate to lead the next generation of kidney research with well-honed skills in animal physiology and molecular biology. This will setup the candidate to meet his long-term career coal of becoming an independent investigator focusing on the cellular and molecular causes of hypertension and renal injury.