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.