Hypothalamic Paraventricular Nucleus Gαi ₂ (Guanine Nucleotide–Binding Protein Alpha Inhibiting Activity Polypeptide 2) Protein–Mediated Neural Control of the Kidney and the Salt Sensitivity of Blood Pressure

We have previously reported that in salt-resistant rat phenotypes brain, Gαi 2 (guanine nucleotide–binding protein alpha inhibiting activity polypeptide 2) proteins are required to maintain blood pressure and sodium balance. However, the impact of hypothalamic paraventricular nucleus (PVN) Gαi 2 proteins on the salt sensitivity of blood pressure is unknown. Here, by the bilateral PVN administration of a targeted Gαi 2 oligodeoxynucleotide, we show that PVN-specific Gαi 2 proteins are required to facilitate the full natriuretic response to an acute volume expansion (peak natriuresis [μeq/min] scrambled (SCR) oligodeoxynucleotide 41±3 versus Gαi 2 oligodeoxynucleotide 18±4; P <0.05) via a renal nerve-dependent mechanism. Furthermore, in response to chronically elevated dietary sodium intake, PVN-specific Gαi 2 proteins are essential to counter renal nerve-dependent salt-sensitive hypertension (mean arterial pressure [mm Hg] 8% NaCl; SCR oligodeoxynucleotide 128±2 versus Gαi 2 oligodeoxynucleotide 147±3; P <0.05). This protective pathway involves activation of PVN Gαi 2 signaling pathways, which mediate sympathoinhibition to the blood vessels and kidneys (renal norepinephrine [pg/mg] 8% NaCl; SCR oligodeoxynucleotide 375±39 versus Gαi 2 oligodeoxynucleotide 850±27; P <0.05) and suppression of the activity of the sodium chloride cotransporter assessed as peak natriuresis to hydrochlorothiazide. Additionally, central oligodeoxynucleotide-mediated Gαi 2 protein downregulation prevented PVN parvocellular neuron activation, assessed by FosB immunohistochemistry, in response to increased dietary salt intake. In our analysis of the UK BioBank data set, it was observed that 2 GNAI2 single nucleotide polymorphism (SNP) (rs2298952, P =0.041; rs4547694, P =0.017) significantly correlate with essential hypertension. Collectively, our data suggest that selective targeting and activation of PVN Gαi 2 proteins is a novel therapeutic approach for the treatment of salt-sensitive hypertension.