The number of people in the US with hypertension (HTN) is increasing and now almost 1 in 2 adults have the #1 contributor to cardiovascular-renal disease. Of these, almost 50% have salt-sensitive hypertension (SSHTN). There is a critical need for targeted therapies that can reduce the detrimental cardiovascular-renal effects of HTN and SSHTN. Our long-term goal is to develop a safe and effective therapeutic for HTN and SSHTN that targets renal lymphatic vessels. The objectives of this application are to determine the role that renal lymphatics play in renal immune cell accumulation and inflammation in HTN and SSHTN and whether modulating renal lymphatics can reduce renal injury and blood pressure. The central hypotheses are that (1) pro-hypertensive stimuli (salt, angiotensin II, ADMA) cause immune cell activation, infiltration, and inflammation in the kidney which leads to a compensatory increase in renal lymphatics, and (2) that further augmenting renal lymphatics is sufficient to attenuate renal inflammation and injury and HTN and SSHTN. Our preliminary data support these hypotheses as there are increased numbers of both immune cells and lymphatic vessels in the kidneys of mice with three different forms of HTN, and that genetically augmenting lymphatics only in the kidney prevents renal inflammation and all forms of HTN. We propose 2 Specific Aims. Specific Aim 1: Determine how renal lymphatics are altered in HTN and SSHTN and the mechanisms involved. Our working hypothesis is that renal lymphatic vessels are increased in a compensatory manner in mice with HTN and SSHTN and this is due to activated immune cell infiltration but not elevated blood pressure. Specific Aim 2: Determine how further augmenting renal lymphatics affects renal inflammation and HTN and SSHTN. Our working hypothesis is that significantly increasing renal lymphatic vessels in mice will both prevent and treat HTN and SSHTN by reducing renal immune cell accumulation, inflammation, and injury. Completion of the aims will determine the role of renal lymphatics in hypertension and whether they are a target for anti-hypertensive therapy. (AHA Program: Transformational Project Award)
