Role of Renal Lymphatics in Blood Pressure Regulation

项目摘要/摘要 近1/2的美国人会患上高血压(HTN)，而这些人中有一半会患上盐敏症 高血压(SSHTN)。精准医学和对抗心血管和肾脏的新疗法 HTN和SSHTN的并发症是迫切需要的。我们的长期目标是发展一种安全有效的 针对肾淋巴管的治疗，以减少肾脏损伤和HTN。这样做的目的是 应用是确定肾脏淋巴管在肾脏免疫细胞聚集和 HTN中的炎症反应以及增加肾脏淋巴管是否可以减少肾脏损伤和血压。HTN 与活化的免疫细胞渗入肾脏有关，导致间质炎症和肾脏 受伤。炎症的消退包括增加淋巴管以清除间质免疫。 细胞和液体，但淋巴反应不足导致持续的炎症和组织损伤。 促炎症免疫细胞在肾脏中的聚集在HTN中起着关键作用；然而， HTN中的肾淋巴管尚不清楚。中心假设是(1)HTN刺激(盐，血管紧张素II， 不对称二甲基精氨酸)引起肾脏免疫细胞活化、渗透和炎症。 有助于肾淋巴管的代偿性增加，(2)肾间质液中HTN的直接刺激 影响肾脏淋巴细胞的生物学和功能，以及(3)进一步增强肾脏淋巴管足以 减轻肾损伤和HTN。最近的出版物和初步数据支持这些假说。这个 假说将通过3个具体目标来检验：(目标1)确定HTN和肾淋巴管如何受到影响 涉及的机制；(目标2)确定HTN刺激如何直接影响淋巴细胞生物学和 目的3)确定诱导肾脏淋巴管生成如何影响肾脏炎症和HTN。 小鼠肾脏淋巴管的药理和遗传扰动的各种组合以及 将使用淋巴细胞和分离血管中的分子机制进行检查。这项研究还将 检查患有和不患有HTN的人的肾脏淋巴管，并开发和测试肾脏特异的 诱导淋巴管生成的纳米颗粒。本研究的创新之处在于阐明了 肾脏中的淋巴管在肾脏炎症和血压调节中的作用 如何增加肾脏淋巴管可以减少肾脏损伤和HTN。技术创新包括 开发独特的转基因小鼠和肾脏特异性淋巴管生成纳米颗粒。这一贡献 将具有重要意义，因为这一结果可能为临床医生提供一种改善肾脏健康和 在美国约1.48亿患有HTN的成年人中，有一些人的血压较低。

PROJECT SUMMARY/ABSTRACT Almost 1 in 2 Americans will develop hypertension (HTN) while half of these people will develop salt-sensitive hypertension (SSHTN). Precision medicine and novel therapies that combat the cardiovascular and renal complications of HTN and SSHTN are critically needed. The long-term goal is to develop a safe and effective therapeutic that targets renal lymphatic vessels to reduce renal injury and HTN. The objectives of this application are to determine the role that renal lymphatics play in renal immune cell accumulation and inflammation in HTN and whether increasing renal lymphatics can reduce renal injury and blood pressure. HTN is associated with activated immune cell infiltration into the kidney leading to interstitial inflammation and renal injury. The resolution of inflammation involves an increase in lymphatic vessels to clear the interstitial immune cells and fluid, but inadequate lymphatic responses result in persistent inflammation and tissue injury. Accumulation of pro-inflammatory immune cells in the kidney plays a key role in HTN; however, the role of renal lymphatics in HTN is unknown. The central hypotheses are that (1) HTN stimuli (salt, angiotensin II, asymmetric dimethylarginine) cause immune cell activation, infiltration, and inflammation in the kidney which contributes to a compensatory increase in renal lymphatics, (2) HTN stimuli in the renal interstitial fluid directly affects renal lymphatic cell biology and function, and (3) that further augmenting renal lymphatics is sufficient to attenuate renal injury and HTN. Recent publications and preliminary data support these hypotheses. The hypotheses will be tested by 3 specific aims: (Aim 1) Determine how renal lymphatics are affected in HTN and the mechanisms involved; (Aim 2) Determine how HTN stimuli directly impact lymphatic cell biology and function; and (Aim 3) Determine how inducing renal lymphangiogenesis affects renal inflammation and HTN. Various combinations of pharmacologic and genetic perturbations of renal lymphatics in mice as well as the examination of molecular mechanisms in lymphatic cells and isolated vessels will be used. The study will also examine renal lymphatics in humans with and without HTN as well as develop and test a kidney-specific nanoparticle that induces lymphangiogenesis. The innovation of the proposed research lies in the elucidation of the role that lymphatic vessels in the kidney play in renal inflammation and blood pressure regulation and how augmenting renal lymphatics can reduce kidney injury and HTN. Technical innovation includes the development of unique transgenic mice and a kidney-specific lymphangiogenic nanoparticle. This contribution will be significant because the results may provide clinicians with a new strategy to improve kidney health and lower blood pressure in some of the ~148 million adults in the US with HTN.