AUTHOR=Amraei Razie , Moreira Jesse D. , Wainford Richard D. 

TITLE=Central Gαi2 Protein Mediated Neuro-Hormonal Control of Blood Pressure and Salt Sensitivity

JOURNAL=Frontiers in Endocrinology

VOLUME=Volume 13 - 2022

YEAR=2022

URL=https://www.frontiersin.org/journals/endocrinology/articles/10.3389/fendo.2022.895466

DOI=10.3389/fendo.2022.895466

ISSN=1664-2392

ABSTRACT=Hypertension, a major public health issue, is estimated to contribute to 10% of all deaths worldwide. Further, the salt sensitivity of blood pressure is a critical risk factor in hypertension. The hypothalamic paraventricular nucleus (PVN) coordinates neuro-hormonal responses to alterations in plasma sodium and osmolality and multiple G Protein-Coupled Receptors (GPCRs) are involved in fluid and electrolyte homeostasis. In acute animal studies, our laboratory has shown that central Gαi/o proteins mediate hypotensive and bradycardic responses and that Gz/q, proteins mediate the release of AVP and subsequent diuretic responses. Extending these studies, our laboratory has shown that central Gαi2 proteins mediate hypotensive, sympathoinhibitory and natriuretic responses to acute pharmacological activation of GPCRs and in response to acute physiological challenges. In addition, following chronically elevated dietary sodium intake, salt resistant rats demonstrate site-specific PVN upregulation of Gαi2 proteins, resulting in sympathoinhibition and normotension. In contrast, chronic dietary sodium challenges in salt sensitive animals result in a failure of sympathoinhibition and exaggerated pressor responses, evoking salt sensitive hypertension. Using in situ hybridization, we observed that Gαi2 expressing neurons in parvocellular division of the PVN strongly (85%) colocalize with GABAergic neurons. Our data suggest that central Gαi2 protein-dependent responses to volume expansion and elevated dietary sodium intake are mediated by the peripheral sensory afferent renal nerves and do not depend on the AV3V sodium sensitive region or the actions of central angiotensin II type 1 receptors. Our human genomic studies have identified three GNAI2 single nucleotide polymorphisms (SNPs) as potential biomarkers in individuals with salt sensitivity and essential hypertension. Collectively, PVN Gαi2 proteins-gated pathways appear to be highly conserved in salt resistance to counter the effects of acute and chronic challenges to fluid and electrolyte homeostasis on blood pressure via a renal sympathetic nerve-dependent mechanism.