In the past several years, research from our laboratory and others has shown that innate and adaptive immunity play critical roles in the genesis of hypertension. The major hypothesis of this project is that the central nervous system coordinates actions of T cells, macrophages and dendritic cells, which in turn affect the vasculature and kidney to raise blood pressure. Studies in the past funding cycle indicate that actions of angiotensin II on circumventricular organs (CVOs) and in particular the subfornical organ (SFO) activate T cells and entry of these cells into the kidney and vasculature, where they promote vascular remodeling, vasoconstriction, salt and volume retention and ultimately blood pressure elevation. We have recently found that CD8+ T cells have a predominant role in the initial (first 2 week) response to angiotensin II and DOCA-salt challenge, and that mice lacking these cells display blunted hypertensive responses to angiotensin II and do not retain sodium and volume in response to angiotensin II. We propose that sympathetic stimuli, acting either on the kidney or secondary lymphoid organs activate dendritic cells (DCs), in part by stimulating DCs to produce reactive oxygen species (ROS) production. By deleting p22phox in the SFO using cre-lox technology, we will prevent the central actions of angiotensin II, and will conversely enhance the central actions of ang II by deleting SOD3 in the SFO. These interventions will determine if the actions of ang II on the SFO are critical for DC and renal CD8+ T cell activation. We will also examine if DC activation occurs predominantly in the spleen or in the kidney by performing selective renal denervation. Preliminary data indicate that angiotensin II increases DC superoxide production by 6 fold, largely via the Nox2 based NADPH oxidase.
In aim 2, we will determine if central actions of angiotensin II promote DC ROS production and to perform studies to determine how this promotes CD8+ T cell activation. Bone marrow transplant of Nox2-/- cells will provide information regarding the role of DC Nox2 in hypertension. Finally, we will examine the role of memory CD8+ T cells in responses to repeated challenges with angiotensin II. These studies will focus on the roles of interactions between CD27 and CD70 and the roles of signals derived from CD4+ cells in CD8+ memory cell formation. Overall, these studies promise to further our understanding of hypertension and provide new therapeutic options for this common and difficult to treat disease.
The sympathetic nervous system is well known to regulate blood pressure. Our research suggests that sympathetic nerves influence inflammation, which in turn alters blood vessel and kidney function, promoting hypertension. In this project, we will seek to understand this more completely, and to develop novel strategies for treatment of this devastating disease.
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