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

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 for the development of 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 subunit protein signal transduction mediates hypotensive and bradycardic responses and that Gz/q, proteins mediate the release of arginine vasopressin (AVP) and subsequent aquaretic responses to acute pharmacological stimuli. Extending these studies, our laboratory has shown that central Gαi₂ proteins selectively mediate the hypotensive, sympathoinhibitory and natriuretic responses to acute pharmacological activation of GPCRs and in response to acute physiological challenges to fluid and electrolyte balance. In addition, following chronically elevated dietary sodium intake, salt resistant rats demonstrate site-specific and subunit-specific upregulation of Gαi₂ proteins in the PVN, resulting in sympathoinhibition and normotension. In contrast, chronic dietary sodium intake in salt sensitive animals, which fail to upregulate PVN Gαi₂ proteins, results in the absence of dietary sodium-evoked sympathoinhibition and 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 an acute isotonic volume expansion (VE) and elevated dietary sodium intake are mediated by the peripheral sensory afferent renal nerves and do not depend on the anteroventral third ventricle (AV3V) sodium sensitive region or the actions of central angiotensin II type 1 receptors. Our translational human genomic studies have identified three G protein subunit alpha I2 (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.

Keywords: Gαi2 proteins; hypertension; paraventricular nucleus; renal nerves; salt sensitivity.

Figure 1

Schematic representation of the canonical intracellular Gα subunit signal transduction pathways activated following ligand binding at G-protein Coupled Receptors (GPCRs). The specificity of Gαi/o, Gαs, Gαz, and Gαq subunit activation in downstream signaling pathways is shown. As illustrated dissociation of Gαz and Gαi/o subunits reduces cyclic AMP (cAMP) and GTP-bound Gαs increases intracellular cAMP levels. Activation of Gαq subunits evokes increased phospholipase C (PLC) signaling activity. Image was generated using BioRender.

Figure 2

Schematic representation of the proposed physiological role of paraventricular nucleus (PVN) Gαi₂ proteins in salt resistance. In response to high dietary-sodium intake, upregulation of PVN Gαi₂ proteins acts as peripherally sensed sodium-responsive “anti-hypertensive” pathway that mediates systemic sympathoinhibition, natriuresis and central anti-inflammatory responses to maintain normotension and a salt resistant phenotype. Image was generated using BioRender.

Figure 3

Schematic representation of the proposed physiological role of paraventricular nucleus (PVN) Gαi₂ proteins in the development of the salt sensitivity of blood pressure. Failure to upregulate paraventricular nucleus (PVN) Gαi₂ proteins in response to elevated dietary sodium intake causes renal nerve-dependent sympathoexcitation, renal sodium retention and neuroinflammation resulting in the development of the salt sensitivity of blood pressure. Image was generated using BioRender.

Figure 4

Schematic representation of upregulation of PVN Gαi₂ protein-dependent responses to elevated dietary sodium intake in salt resistance. Upregulation of PVN specific Gαi₂ is mediated by the peripheral sensory afferent renal nerves and does not depend on the AV3V sodium sensitive region or actions of central angiotensin II type 1 receptors. Image was generated using BioRender.

Figure 5

Schematic representation of neuroanatomical localization of Gαi2 mRNA-expressing neurons in PVN. Gαi2 mRNA expressing neurons are highly localized within the parvocellular region of the PVN and strongly colocalize with GABAergic neurons. Image was generated using BioRender.