Gαi ₂ -Protein–Mediated Signal Transduction

Abstract

Excess dietary salt-intake is an established cause of hypertension. At present our understanding of the neuro-pathophysiology of salt-sensitive hypertension is limited by a lack of identification of the central nervous system mechanisms that modulate sympathetic outflow and blood pressure in response to dietary salt-intake. We hypothesized that impairment of brain Gαi2 protein-gated signal transduction pathways would result in increased sympathetically mediated renal sodium retention, thus promoting the development of salt-sensitive hypertension. To test this hypothesis, naïve or renal denervated Dahl salt-resistant and Dahl salt-sensitive rats were assigned to receive a continuous intracerebroventricular control scrambled or a targeted Gαi2 oligodeoxynucleotide infusion, and naïve Brown Norway and 8-congenic Dahl salt-sensitive rats, were fed a 21-day normal or high-salt diet. High salt-intake did not alter blood pressure, suppressed plasma norepinephrine, and evoked a site-specific increase in hypothalamic paraventricular nucleus Gαi2 protein levels in naïve Brown-Norway, Dahl salt-resistant and scrambled oligodeoxynucleotide-infused Dahl salt-resistant, but not Dahl salt-sensitive rats. In Dahl salt-resistant rats Gαi2 down-regulation evoked rapid renal nerve-dependent hypertension, sodium retention and sympathoexcitation. In Dahl salt-sensitive rats, Gαi2 down-regulation exacerbated salt-sensitive hypertension via a renal nerve-dependent mechanism. Congenic-8 Dahl salt-sensitive rats exhibited sodium-evoked paraventricular nucleus specific Gαi2 protein up-regulation and attenuated hypertension, sodium retention and global sympathoexcitation compared to Dahl salt-sensitive rats. These data demonstrate that paraventricular nucleus Gαi2 protein-gated pathways represent a conserved central molecular pathway mediating sympathoinhibitory renal-nerve dependent responses evoked to maintain sodium homeostasis and a salt-resistant phenotype. Impairment of this mechanism contributes to the development of salt-sensitive hypertension.

Role of the afferent renal nerves in sodium homeostasis and blood pressure regulation in rats

“…A radiotelemetry probe (PA-C40, DSI, New Brighton, MN, USA) was implanted into the abdominal aorta via the left femoral artery and all animals recovered for 5-7 days prior to collection of baseline blood pressure data (Brouwers, Smolders, Wainford, & Dupont, 2015;Foss et al, 2015;Wainford, Carmichael, Pascale, & Kuwabara, 2015). ketamine, 3 mg kg −1 I.P.…”

Hypothalamic Signaling Mechanisms in Hypertension

“…A recent focus has been on the identification of potential mechanisms maintaining salt-resistance [ 39 – 41 ]. In the salt-resistant SD rat, in response to changes in dietary sodium intake, there is an endogenous PVN-specific increase (sodium excess) or decrease (sodium restriction) in guanine nucleotide binding protein alpha inhibiting activity binding polypeptide 2 (Gαi 2 ) protein expression [ 39 ].…”

“…Acute and chronic downregulation of brain Gαi 2 proteins in high salt-challenged SD rats, which prevents endogenous PVN Gαi 2 protein upregulation, evokes sodium retention, global sympathoexcitation, and elevated blood pressure [ 39 , 40 ] suggesting a critical role of these proteins in maintaining salt-resistance. An endogenous sodium-evoked increase in PVN Gαi 2 protein expression has been documented in multiple salt-resistant phenotypes, as has a failure of this response in the DSS rat [ 41 ]. Further, brain Gαi 2 proteins are required to maintain salt-resistance, via a renal nerve-dependent pathway, in the salt-resistant SD and DSR rat [ 40 , 41 ].…”

“…An endogenous sodium-evoked increase in PVN Gαi 2 protein expression has been documented in multiple salt-resistant phenotypes, as has a failure of this response in the DSS rat [ 41 ]. Further, brain Gαi 2 proteins are required to maintain salt-resistance, via a renal nerve-dependent pathway, in the salt-resistant SD and DSR rat [ 40 , 41 ]. Collectively, PVN-specific Gαi 2 -subunit protein–gated signal transduction pathways represent a novel central molecular signal transduction pathway that acts to regulate central sympathetic outflow to the kidneys in response to alterations in salt intake to maintain a salt-resistant phenotype [ 39 – 41 ].…”

Downregulation of Endogenous Hydrogen Sulfide Pathway Is Involved in Mitochondrion-Related Endothelial Cell Apoptosis Induced by High Salt

“…Previous studies indicated that high-salt insult promoted hypertension in association with activating angiotensin-aldosterone system [ 1 ], damaging renal natriuresis function [ 2 ], enhancing sympathetic activity [ 3 ], increasing the extracellular capacity, and eventually leading to sodium and water retention [ 4 ]. In addition, high salt could destroy the transfer passage of paraventricular nucleus G α i-protein gating signals [ 5 ]. However, the mechanisms for high-salt-induced hypertension remain unclear.…”