DAMPs, vasa recta pericytes, pressure-natriuresis and hypertension

项目总结P3，O‘Connor 在美国，约33%的成年人患有高血压，不分性别，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。与损害相关 分子模式(DAMP)是由受损细胞和免疫细胞释放的。高迁移率族蛋白1 (HMGB1)是湿的，高血压患者循环中HMGB1水平升高。一位批评者 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的目标是确定阻滞剂是否作用于肾髓质循环 导致血压-钠尿的前高血压转变。研究基于一种新的概念，即 自发性的直肠血管降支(DVR)周细胞节律性收缩有助于防止红色 血细胞(RBC)阻塞这些长的、低压的毛细血管。我们的中心假设是 HMGB1刺激DVR内皮细胞在低剪切状态下不适当地产生一氧化氮(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RBC聚集。此外，自发性高血压患者循环中HMGB1水平的升高可能会刺激慢性 作用于TLR4受体的DVR内皮细胞的炎症和激活。这也将促进 通过减缓免疫细胞的运动或通过增加继发性血管血细胞压积来阻塞血管 血浆泄漏。DVR的RBC闭塞会导致周围髓血管的稀疏， 血压受损--钠尿和高血压。我们将通过三个具体目标来检验我们的假设：1)检验 低流量刺激节律性周细胞收缩并被HMGB1诱导抑制的假说 NO产生，2)检验自发性高血压患者循环中湿气水平升高促进慢性高血压的假设 血管直肠内皮细胞的激活和血管炎症，以及3)检验以下假设 促进DVR中的RBC聚集，这有助于髓质毛细血管的稀疏，这是一种促进 肾内压、钠尿和高血压的高血压转变。项目3与以下项目高度协同 其他项目，并依赖于所有核心的成功完成我们的目标。P1将利用肾脏 P3实验中的血管。P2和P3将合作研究黏附分子和 循环免疫细胞对骨髓循环的影响以及髓微血管的凋亡 有助于女性更大的Tregs。拟议的研究采用了高度综合的方法。 结合体内整体动物研究和体外髓循环测量，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一种机械联系 被认为在高血压的发展中起关键作用；激活先天免疫系统和肾脏 并有可能影响治疗，不仅是高血压，而且是一些 发生DVR阻塞的疾病。

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.