Role of Renal Lymphatics in Blood Pressure Regulation

项目总结/摘要 几乎每2个美国人中就有1人会患上高血压（HTN），而这些人中有一半会患上盐敏感症。 高血压（SSHTN）。精准医疗和新疗法，对抗心血管和肾脏疾病 HTN和SSHTN的并发症是非常需要的。长期目标是开发一种安全有效的 靶向肾淋巴管以减少肾损伤和HTN的治疗剂。这一目标 应用的目的是确定肾促红细胞生成剂在肾免疫细胞积累中的作用， 高血压性肾病的炎症反应以及增加肾功能是否能减轻肾损伤和降低血压。HTN 与活化的免疫细胞浸润到肾脏中相关，导致间质性炎症和肾损害。 损伤炎症的解决涉及淋巴管的增加，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。 肾脏中促炎免疫细胞的积累在HTN中起关键作用;然而， 尚不清楚HTN中的肾脏代谢。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）引起肾脏中的免疫细胞活化、浸润和炎症， 有助于肾功能代偿性增加，（2）肾间质液中的HTN刺激直接 影响肾淋巴细胞生物学和功能，以及（3）进一步增强肾功能足以 减轻肾损伤和HTN。最近的出版物和初步数据支持这些假设。的 假设将通过3个具体目标进行检验：（目标1）确定HTN中肾功能如何受到影响， （目的2）确定HTN刺激如何直接影响淋巴细胞生物学， 目的3：研究肾淋巴管生成对肾脏炎症和高血压的影响。 小鼠中肾脏代谢的药理学和遗传学扰动的各种组合以及 将使用淋巴细胞和分离的血管中的分子机制的检查。该研究还将 检查有和没有HTN的人的肾功能，以及开发和测试肾脏特异性 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 肾脏淋巴管在肾脏炎症和血压调节中的作用， 增强肾功能如何减少肾损伤和HTN。技术创新包括 开发独特的转基因小鼠和肾特异性淋巴管生成纳米颗粒。这一贡献 将是重要的，因为结果可能为临床医生提供一个新的策略，以改善肾脏健康， 降低美国约1.48亿HTN成年人的血压。

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.