Tags

Type your tag names separated by a space and hit enter

Hypothalamic Paraventricular Nucleus Gαi2 (Guanine Nucleotide-Binding Protein Alpha Inhibiting Activity Polypeptide 2) Protein-Mediated Neural Control of the Kidney and the Salt Sensitivity of Blood Pressure.
Hypertension. 2020 Apr; 75(4):1002-1011.H

Abstract

We have previously reported that in salt-resistant rat phenotypes brain, Gαi2 (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) Gαi2 proteins on the salt sensitivity of blood pressure is unknown. Here, by the bilateral PVN administration of a targeted Gαi2 oligodeoxynucleotide, we show that PVN-specific Gαi2 proteins are required to facilitate the full natriuretic response to an acute volume expansion (peak natriuresis [μeq/min] scrambled (SCR) oligodeoxynucleotide 41±3 versus Gαi2 oligodeoxynucleotide 18±4; P<0.05) via a renal nerve-dependent mechanism. Furthermore, in response to chronically elevated dietary sodium intake, PVN-specific Gαi2 proteins are essential to counter renal nerve-dependent salt-sensitive hypertension (mean arterial pressure [mm Hg] 8% NaCl; SCR oligodeoxynucleotide 128±2 versus Gαi2 oligodeoxynucleotide 147±3; P<0.05). This protective pathway involves activation of PVN Gαi2 signaling pathways, which mediate sympathoinhibition to the blood vessels and kidneys (renal norepinephrine [pg/mg] 8% NaCl; SCR oligodeoxynucleotide 375±39 versus Gαi2 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 Gαi2 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 Gαi2 proteins is a novel therapeutic approach for the treatment of salt-sensitive hypertension.

Authors+Show Affiliations

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.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 Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA (C.L.P., D.R.K.).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.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 Pharmacology and Experimental Therapeutics, Louisiana State University Health Sciences Center, New Orleans, LA (C.L.P., D.R.K.).Department of Anatomy & Neurobiology (D.L.R.), Boston University School of Medicine, MA.Division of Endocrinology, Diabetes, Hypertension, Brigham and Women's, Harvard Medical School, Boston, MA (J.S.W.).Department of Physiology and Anatomy, University of North Texas Health Science Center, Fort Worth, TX (J.T.C.).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.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

32148128

Citation

Carmichael, Casey Y., et al. "Hypothalamic Paraventricular Nucleus Gαi2 (Guanine Nucleotide-Binding Protein Alpha Inhibiting Activity Polypeptide 2) Protein-Mediated Neural Control of the Kidney and the Salt Sensitivity of Blood Pressure." Hypertension (Dallas, Tex. : 1979), vol. 75, no. 4, 2020, pp. 1002-1011.
Carmichael CY, Kuwabara JT, Pascale CL, et al. Hypothalamic Paraventricular Nucleus Gαi2 (Guanine Nucleotide-Binding Protein Alpha Inhibiting Activity Polypeptide 2) Protein-Mediated Neural Control of the Kidney and the Salt Sensitivity of Blood Pressure. Hypertension. 2020;75(4):1002-1011.
Carmichael, C. Y., Kuwabara, J. T., Pascale, C. L., Moreira, J. D., Mahne, S. E., Kapusta, D. R., Rosene, D. L., Williams, J. S., Cunningham, J. T., & Wainford, R. D. (2020). Hypothalamic Paraventricular Nucleus Gαi2 (Guanine Nucleotide-Binding Protein Alpha Inhibiting Activity Polypeptide 2) Protein-Mediated Neural Control of the Kidney and the Salt Sensitivity of Blood Pressure. Hypertension (Dallas, Tex. : 1979), 75(4), 1002-1011. https://doi.org/10.1161/HYPERTENSIONAHA.119.13777
Carmichael CY, et al. Hypothalamic Paraventricular Nucleus Gαi2 (Guanine Nucleotide-Binding Protein Alpha Inhibiting Activity Polypeptide 2) Protein-Mediated Neural Control of the Kidney and the Salt Sensitivity of Blood Pressure. Hypertension. 2020;75(4):1002-1011. PubMed PMID: 32148128.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Hypothalamic Paraventricular Nucleus Gαi2 (Guanine Nucleotide-Binding Protein Alpha Inhibiting Activity Polypeptide 2) Protein-Mediated Neural Control of the Kidney and the Salt Sensitivity of Blood Pressure. AU - Carmichael,Casey Y, AU - Kuwabara,Jill T, AU - Pascale,Crissey L, AU - Moreira,Jesse D, AU - Mahne,Sarah E, AU - Kapusta,Daniel R, AU - Rosene,Douglas L, AU - Williams,Jonathan S, AU - Cunningham,J Thomas, AU - Wainford,Richard D, Y1 - 2020/03/09/ PY - 2020/3/10/pubmed PY - 2020/3/10/medline PY - 2020/3/10/entrez KW - G alpha i 2 proteins KW - hypertension KW - norepinephrine KW - paraventricular nucleus KW - renal sympathetic nerves SP - 1002 EP - 1011 JF - Hypertension (Dallas, Tex. : 1979) JO - Hypertension VL - 75 IS - 4 N2 - We have previously reported that in salt-resistant rat phenotypes brain, Gαi2 (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) Gαi2 proteins on the salt sensitivity of blood pressure is unknown. Here, by the bilateral PVN administration of a targeted Gαi2 oligodeoxynucleotide, we show that PVN-specific Gαi2 proteins are required to facilitate the full natriuretic response to an acute volume expansion (peak natriuresis [μeq/min] scrambled (SCR) oligodeoxynucleotide 41±3 versus Gαi2 oligodeoxynucleotide 18±4; P<0.05) via a renal nerve-dependent mechanism. Furthermore, in response to chronically elevated dietary sodium intake, PVN-specific Gαi2 proteins are essential to counter renal nerve-dependent salt-sensitive hypertension (mean arterial pressure [mm Hg] 8% NaCl; SCR oligodeoxynucleotide 128±2 versus Gαi2 oligodeoxynucleotide 147±3; P<0.05). This protective pathway involves activation of PVN Gαi2 signaling pathways, which mediate sympathoinhibition to the blood vessels and kidneys (renal norepinephrine [pg/mg] 8% NaCl; SCR oligodeoxynucleotide 375±39 versus Gαi2 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 Gαi2 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 Gαi2 proteins is a novel therapeutic approach for the treatment of salt-sensitive hypertension. SN - 1524-4563 UR - https://www.unboundmedicine.com/medline/citation/32148128/Hypothalamic_Paraventricular_Nucleus_Gαi2__Guanine_Nucleotide_Binding_Protein_Alpha_Inhibiting_Activity_Polypeptide_2__Protein_Mediated_Neural_Control_of_the_Kidney_and_the_Salt_Sensitivity_of_Blood_Pressure_ L2 - http://www.ahajournals.org/doi/full/10.1161/HYPERTENSIONAHA.119.13777?url_ver=Z39.88-2003&amp;rfr_id=ori:rid:crossref.org&amp;rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -
Try the Free App:
Prime PubMed app for iOS iPhone iPad
Prime PubMed app for Android
Prime PubMed is provided
free to individuals by:
Unbound Medicine.