Role of bradykinin 1 receptor in neurogenic hypertension
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Overview
abstract
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Hypertension 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. The kinins, particularly bradykinin (BK) and Lys-BK, are vasoactive peptides which are present in the brain and play important roles in blood pressure regulation and inflammation. There is evidence for cross-talk between the components of RAS and the bradykinin receptors 1 (B1R) and 2 (B2R) of the kallikrein-kinin system. However, the role of bradykinin receptors in neurogenic hypertension and their interaction with RAS in the brain, and molecular mechanisms involved have not been studied. The central hypothesis is that activation of B1R in the brain results in increased inflammatory cytokine production and oxidative stress, leading to neurogenic hypertension. This hypothesis will be tested by pursuing following specific aims: (1) identify the causal role of B1R in the neurogenic hypertension by testing the hypothesis that activation of B1R in the brain induces hypertension, whereas, central blockade of B1R attenuates hypertension; (2) determine whether B1R signaling-induced oxidative stress results in damage to mitochondrial integrity and mitochondrial biogenesis, leading to hypertension; (3) investigate the interaction of B1R with RAS components in the brain in neurogenic hypertension. In terms of approaches, we will use genetically engineered mouse models combined with state of the art molecular, pharmacological and physiological tools to investigate the contribution of central B1R in DOCA-salt-induced model of neurogenic hypertension. The expected outcomes of these studies will clarify the role of BK peptides in hypertension, identify cellular and molecular mechanisms involved, add to the knowledge of our current understanding of neurogenic hypertension, and provide new insights for the clinical treatment of hypertension. These studies are expected to have a broad positive impact because kinin receptor mediated neural regulation of blood pressure is relevant to other cardiovascular diseases including diabetes, atherosclerosis, as well as neurodegenerative diseases such as Alzheimer?s disease and multiple sclerosis.
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