Hypertension (HTN) remains an important medical and public health issue in the United States. Most current therapeutic measures are targeted against the peripheral renin-angiotensin system (RAS). These therapies have reduced the morbidity and mortality in hypertensive patients. However, the long-term prognosis in patients with hypertension remains poor, and new therapeutic approaches are needed. We previously showed that inhibiting brain ADAM17 (A Disintegrin and Metalloprotease) or angiotensin II type 1 receptor (AT1R) upregulation will reduce the progression of HTN. Our recent work indicates that kinin B1 receptor (B1R) activation leads to elevated inflammation in key autonomic brain regions such as the hypothalamic paraventricular nucleus (PVN) and pharmacological blockade or genetic deletion of B1R attenuates neurogenic HTN. In addition, our preliminary data shows that B1R expression is elevated in the PVN of hypertensive human subjects. Evidence suggests that elevated kininase I (carboxypeptidase, CPN/CPM that cleaves bradykinin into des-Arg9- bradykinin, an endogenous agonist for B1R) levels account for increasing endogenous levels of B1R agonists, leading to subsequent upregulation and activation of B1R. Stimulation of B1R results in ADAM17 activation that in turn transactivates epidermal growth factor receptor (EGFR). However, the exact signal transduction mechanisms of B1R and Kininase I, and interactions of AT1R, ADAM17 and EGFR with B1R, in HTN are not clear. Therefore, in this proposal, we test the central hypothesis that the blockade of B1R signaling in the brain reduces inflammation and oxidative stress, thereby decreasing sympathoexcitation, leading to attenuation of neurogenic HTN. This hypothesis will be tested by following specific aims: (1) Determine whether targeted blockade of B1R signaling attenuates neurogenic HTN, (2) Identify the causal role of central B1R activation to the development of neurogenic HTN, and (3) Elucidate the signaling mechanisms and functional interactions between B1R and AT1R/ADAM17/EGFR in the PVN in neurogenic HTN. In terms of approaches, we will use state-of-the-art in vitro and in vivo pharmacological and molecular methods combined with novel and unique genetic models to investigate the signaling mechanisms of B1R in HTN. This project will identify novel and vital role of B1R signaling in HTN and provide insights for developing new therapeutics for the treatment of human neurogenic HTN.
Hypertension is a major risk factor for cardiovascular diseases such as stroke, heart failure and renal failure. With a greater than 33% prevalence rate in the United States, hypertension remains an increasingly important medical and public health issue. In this proposal, we aim to develop a novel therapeutic approach based on kinin B1 receptor blockade to treat neurogenic hypertension.