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The Brain Renin-Angiotensin System in the Regulation of Blood Pressure
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Hypertension, or high blood pressure, affects over one-third of the adult US population and over a billion people globally. Hypertension is the main risk factor for cardiovascular diseases and stroke, demonstrating the importance of blood pressure regulation. The local brain renin-angiotensin system (RAS) has emerged as a key player in the development and pathogenesis of hypertension. However, the mechanisms and localization of this complex cascade of peptides, enzymes, and receptors are not well understood and under debate whether all components are expressed within the brain, especially endogenous prorenin. This dissertation focuses on the role of the brain RAS in the development of salt-sensitive hypertension (SSH) in the subfornical organ (SFO) and the paraventricular nucleus (PVN) of the hypothalamus, key brain nuclei in blood pressure and body fluid homeostasis. We show in this dissertation that renin-a, the endogenously secreted prorenin, is elevated within the SFO after DOCA-Salt treatment (a model for SSH). Ablation of renin-a within SFO neurons is able to attenuate blood pressure and improve autonomic function after the DOCA-Salt challenge. We also clearly show that renin is present within the brain, specifically in glutamatergic and GABAergic neurons. We then utilize advanced single nuclei multiomic sequencing to characterize the RAS within the PVN. We observe the presence of the RAS components within the PVN, primarily in glutamatergic and GABAergic neurons. Interestingly, we show that after DOCA-Salt treatment the neurons undergo a cell-type population shift, with the inhibitory GABAergic neurons switching to the excitatory glutamatergic cell type. We also see this trend in the PRR-expressing neurons, with PRR-neurons shifting to the glutamatergic subtype. Collectively our data support the importance for the brain RAS and glutamatergic neurons in the development and/or maintenance of SSH.