| Autor: |
Carmichael CY; From the Department of Pharmacology and Experimental Therapeutics and The Whitaker Cardiovascular Institute (C.Y.C., J.T.K., J.D.M., S.E.M., R.D.W.), Boston University School of Medicine, MA., Kuwabara JT; From the Department of Pharmacology and Experimental Therapeutics and The Whitaker Cardiovascular Institute (C.Y.C., J.T.K., J.D.M., S.E.M., R.D.W.), Boston University School of Medicine, MA., Pascale CL; Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA (C.L.P., D.R.K.)., Moreira JD; From the Department of Pharmacology and Experimental Therapeutics and The Whitaker Cardiovascular Institute (C.Y.C., J.T.K., J.D.M., S.E.M., R.D.W.), Boston University School of Medicine, MA.; Department of Health Sciences (J.D.M.), Boston University School of Medicine, MA., Mahne SE; From the Department of Pharmacology and Experimental Therapeutics and The Whitaker Cardiovascular Institute (C.Y.C., J.T.K., J.D.M., S.E.M., R.D.W.), Boston University School of Medicine, MA., Kapusta DR; Department of Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA (C.L.P., D.R.K.)., Rosene DL; Department of Anatomy & Neurobiology (D.L.R.), Boston University School of Medicine, MA., Williams JS; Division of Endocrinology, Diabetes, Hypertension, Brigham and Women's, Harvard Medical School, Boston, MA (J.S.W.)., Cunningham JT; Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX (J.T.C.)., Wainford RD; From the Department of Pharmacology and Experimental Therapeutics and The Whitaker Cardiovascular Institute (C.Y.C., J.T.K., J.D.M., S.E.M., R.D.W.), Boston University School of Medicine, MA. |
| Abstrakt: |
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. |
