DAMPs, vasa recta pericytes, pressure-natriuresis and hypertension

DAMP、直肠血管周细胞、压力尿钠和高血压

• 批准号: 10094232
• 负责人: Paul Michael O'Connor
• 金额: $ 38万
• 依托单位: AUGUSTA UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-02-01 至 2023-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10094232
• 关键词: Adult; Affect; Agonist; Animals; Antihypertensive Agents; Apoptosis; Blood Circulation; Blood Vessels; Blood capillaries; Blood flow; Cardiovascular Diseases; Cell Adhesion Molecules; Cell Aggregation; Cells; Chronic; Chronic Kidney Failure; Data; Development; Disease; Endothelial Cells; Erythrocytes; Essential Hypertension; Event; Exposure to; Extravasation; Female; Goals; HMGB1 Protein; Heart failure; Hematocrit procedure; Hypertension; Hypoxia; Immune; Immune system; Impairment; Inbred SHR Rats; Inbred WKY Rats; Infiltration; Inflammation; Infusion procedures; Innate Immune System; Ischemia; Kidney; Knowledge; Leukocytes; Link; Measurement; Mediating; Molecular; Movement; Myocardial Infarction; Natriuresis; Necrosis; Nitric Oxide; Nitric Oxide Synthase; Obstruction; Paracrine Communication; Patients; Pattern; Pericytes; Periodicity; Peripheral arterial disease; Pharmaceutical Preparations; Plasma; Preparation; Process; Production; Protein Isoforms; Rattus; Regulatory T-Lymphocyte; Renal function; Reporting; Risk; Role; Secondary to; Stroke; TLR4 gene; Testing; Therapeutic; Toll-like receptors; Ultrasonography; Vascular blood supply; base; blood pressure regulation; cardiovascular risk factor; cell injury; experimental study; fluorescence imaging; immune activation; improved; in vivo; inflammatory marker; instrument; kidney medulla; kidney vascular structure; normotensive; novel; pressure; prevent; receptor; response; sex; tissue oxygenation; vascular inflammation

PROJECT SUMMARY P3, O'CONNOR Hypertension affects ~33% of adults in the U.S. and regardless of sex, fewer than 40% of hypertensive patients taking medication achieve blood pressure (BP) control to recommended levels. Damage-associated molecular patterns (DAMPs) are released by injured cells and immune cells. High mobility group box 1 protein (HMGB1) is a DAMP, and circulating HMGB1 levels are increased in patients with hypertension. A critical barrier to improving BP control rates is lack of understanding how activation of the innate immune system alters renal function. The goal of P3 is to determine whether DAMPs act on the renal medullary circulation to cause a pro-hypertensive shift in pressure-natriuresis. Studies are based on the novel concept that spontaneously occurring rhythmic contractions of descending vasa recta (DVR) pericytes help prevent red blood cell (RBC) blockage of these long, low pressure capillaries. Our central hypothesis is that is that HMGB1 stimulates inappropriate nitric oxide (NO) production by DVR endothelial cells in low sheer states, which is detrimental as it inhibits spontaneous rhythmic contractions of DVR pericytes that normally act to prevent RBC aggregations. Further, elevated levels of circulating HMGB1 in SHR may stimulate chronic inflammation and activation of the DVR endothelial cells by acting on TLR4 receptors. This would also promote vascular clogging by slowing the movement of immune cells or by increasing vessel hematocrit secondary to plasma leakage. RBC occlusion of DVR then leads to rarefaction of surrounding medullary vasculature, impaired pressure-natriuresis and hypertension. We will test our hypothesis via three specific aims: 1) Test the hypothesis that low flow stimulates rhythmic pericyte contractility and that this is inhibited by HMGB1-induced NO production, 2) Test the hypothesis that elevated levels of circulating DAMPS in SHR promotes chronic activation of vasa-recta endothelial cells and vascular inflammation, and 3) Test the hypothesis that DAMPs promote RBC aggregation in DVR and that this contributes to rarefaction of the medullary capillaries, a pro- hypertensive shift in intrinsic renal pressure natriuresis and hypertension. Project 3 is highly synergistic with the other Projects and is dependent on all Cores for the successful completion of our aims. P1 will utilize renal vessels from experiments in P3. P2 and P3 will collaborate to investigate the role of adhesion molecules and circulating immune cells on the medullary circulation as well as whether apoptosis of medullary microvessels contributes to greater Tregs in females. The proposed studies utilize a highly integrative approach incorporating in vivo whole animal studies and ex vivo measurements of the medullary circulation to rigorously test our hypothesis. Our results will provide a mechanistic link between the seemingly disparate processes thought to be critical in the development of hypertension; activation of the innate immune system and renal medullary ischemia and have the potential to impact the treatment, not only of hypertension, but a number of diseases in which DVR blockage occurs.

项目摘要 P3，奥康纳 高血压影响约 33% 的美国成年人，无论性别如何，只有不到 40% 的高血压患者 服用药物的患者将血压 (BP) 控制在推荐水平。损伤相关 分子模式 (DAMP) 由受损细胞和免疫细胞释放。高迁移率族盒1蛋白 (HMGB1) 是一种 DAMP，高血压患者的循环 HMGB1 水平升高。一个批评的 提高血压控制率的障碍是缺乏对先天免疫系统如何激活的了解 改变肾功能。 P3 的目标是确定 DAMP 是否作用于肾髓质循环以 导致压力尿钠的促高血压转变。研究基于这样一个新颖的概念： 降直血管 (DVR) 周细胞自发发生的节律性收缩有助于预防红细胞 血细胞 (RBC) 堵塞这些长的低压毛细血管。我们的中心假设是 HMGB1 刺激 DVR 内皮细胞在低剪切状态下产生不适当的一氧化氮 (NO)， 这是有害的，因为它抑制了 DVR 周细胞的自发节律性收缩，而 DVR 周细胞通常作用于 防止红细胞聚集。此外，SHR 中循环 HMGB1 水平升高可能会刺激慢性 通过作用于 TLR4 受体来抑制 DVR 内皮细胞的炎症和激活。这也将促进 通过减慢免疫细胞的运动或增加血管血细胞比容继发于血管堵塞 血浆泄漏。 DVR 的红细胞闭塞导致周围髓质脉管系统稀疏， 压力尿钠受损和高血压。我们将通过三个具体目标来检验我们的假设：1）检验 假设低流量刺激节律性周细胞收缩性，并且这种收缩性受到 HMGB1 诱导的抑制 NO 产生，2) 检验 SHR 中循环 DAMPS 水平升高会促进慢性病的假设 血管直肠内皮细胞的激活和血管炎症，以及 3) 检验 DAMP 的假设 促进 DVR 中红细胞聚集，这有助于稀疏髓质毛细血管，这是一种亲 高血压转变为肾内压尿钠排泄和高血压。项目3与 其他项目，并依赖于所有核心来成功完成我们的目标。 P1将利用肾 P3 实验中的船只。 P2和P3将合作研究粘附分子和 循环免疫细胞对髓质循环的影响以及髓质微血管是否凋亡 有助于女性产生更大的 Tregs。拟议的研究采用高度综合的方法 结合体内整体动物研究和髓质循环的离体测量，以严格 检验我们的假设。我们的结果将在看似不同的过程之间提供机械联系 被认为对高血压的发展至关重要；激活先天免疫系统和肾脏 髓质缺血并有可能影响治疗，不仅是高血压，还有许多疾病 发生 DVR 阻塞的疾病。