Document Type
Thesis
Date of Award
2025
Degree Name
Doctor of Philosophy (PhD)
Department
Basic Biomedical Science
First Advisor
Hong Zheng
Abstract
The hypothalamic paraventricular nucleus (PVN) regulates diverse physiological processes for maintaining homeostasis, modulating functions ranging from fluid balance to sympathetic nervous system activity. Due to its integral connections with various autonomic and endocrine systems, the PVN significantly influences cardiovascular and renal function, notably in blood pressure homeostasis and the development and regulation of hypertension. The regulatory capacity of PVN is mediated through several signaling pathways, including those involving G-protein coupled receptor (GPCR) and G- protein signaling. We hypothesized the altered PVN signaling through Gαq/Gαs and regulators like regulator of G-protein signaling 2 (RGS2) pathways affected sympathetic nerve activity and blood pressure regulation in hypertension. We observed that Gαq/Gαs and RGS2 expression in the PVN significantly changed in both genetic (spontaneously hypertensive-SHR) and induced (angiotensin II infusion) hypertensive rats. As we overexpressed RGS2 with adenoviral transfection in the PVN, the hypertensive rats showed a significant reduction in sympathetic activity and blood pressure, with increased sodium excretion and kidney function compared to the control vector groups. Using an RGS2-flox mouse, we generated RGS2 PVN-specific knockdown mice. The RGS2 knockdown mice depicted a significant rise in blood pressure and sodium dysregulation. Our in vivo and vitro study showed that RGS2 modulated protein kinase C (PKC) signaling and calcium influx to affect central angiotensin II-induced sympathoexcitation and high blood pressure. Moreover, we found retrograde tracer- labeled neurons within the PVN after the tracer injection into the kidney to explore the connection between the afferent renal nerve and the brain. Direct renal pelvic stimulation increased blood pressure and neuronal activity in the PVN. We also saw that selective afferent renal nerve denervation significantly decreased sympathetic activity and blood pressure, improved sodium balance, and modulated central pre-autonomic neuronal activity in hypertensive rats. In conclusion, our studies suggest that alterations in PVN Gαq/Gαs and RGS2 pathways influence sympathetic nerve activity, blood pressure and renal sodium homeostasis in hypertension. Kidney-PVN-specific pathways hold promise in achieving more effective blood pressure control by addressing the central mechanisms underlying sympathetic and blood pressure regulation.
Subject Categories
Cellular and Molecular Physiology | Physiology
Keywords
Hypertension RGS2 Signaling Pathways Sympathetic Nervous System
Number of Pages
206
Publisher
University of South Dakota
Recommended Citation
Boomer, Shane Harold, "HYPOTHALAMIC PARAVENTRICULAR NUCLEUS G⍺q/G⍺s AND RGS2 SIGNALING PATHWAYS MEDIATE SYMPATHOEXCITATION AND SODIUM RETENTION IN HYPERTENSION" (2025). Dissertations and Theses. 329.
https://red.library.usd.edu/diss-thesis/329