Neural mechanisms promoting G-alpha-i2 protein dependent salt sensitive hypertension in the Sprague-Dawley rat

Hypertension (HTN) is a critical public health issue estimated to contribute to 10% of deaths worldwide. Additionally, the salt sensitivity of blood pressure, an exaggerated pressor response to elevated dietary sodium intake, is estimated to be present in approximately 50% of the hypertensive population and 25% of the normotensive population. This is a critical problem as the average American consumes roughly three times the daily sodium intake recommended by the American Heart Association. Our laboratory has previously identified a critical role of Hypothalamic Paraventricular Nucleus (PVN) Gαi2 proteins in the maintenance of salt resistance and normotension in the rat. Salt resistant rats such as the Sprague-Dawley (SD) rat site- specifically upregulate these proteins in response to elevated dietary sodium intake to facilitate sympathoinhibition, natriuresis, and normotension. In contrast, in the Dahl Salt Sensitive (DSS) rat, and in salt resistant rats in which this protein is experimentally downregulated, our laboratory has identified the development of renal nerve-dependent sympathoexcitation and salt-sensitive hypertension (ssHTN). However, the neural mechanisms whereby PVN Gαi2 proteins facilitate salt resistance are unclear. In addition, there is a robust literature in other rat models of HTN suggesting that both neuroinflammation in the PVN as well as an imbalance between PVN inhibitory GABAergic and excitatory glutamatergic signaling contribute to elevations in sympathetic outflow to promote HTN. In this study, SD rats infused chronically with either targeted Gαi2 oligodeoxynucleotides (ODNs) or control scrambled (SCR) ODNs and challenged with either normal (0.6% NaCl) or high-salt (4% NaCl) diets were used to demonstrate that 1) PVN microglial activation and associated pro-inflammatory cytokine production contribute to the development of Gαi2 protein dependent ssHTN, 2) sex-dependent PVN microglial-mediated neuroinflammation precedes and likely drives the development of sympathoexcitation following high dietary sodium administration in male but not female Gαi2 protein dependent ssHTN, and 3) PVN GABAergic and glutamatergic signaling is disrupted and imbalanced, favoring excitation over inhibition, following elevated dietary sodium intake in Gαi2 protein dependent ssHTN. Together, these findings shed light on the pathological neural processes that occur in the absence of PVN Gαi2 protein upregulation and reveal potential mechanistic targets in the management of ssHTN