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Inhibition of microglial activation in rats attenuates paraventricular nucleus inflammation in Gαi2 protein-dependent, salt-sensitive hypertension.

Abstract

NEW FINDINGS

• What is the central question of this study? We hypothesized that central inflammatory processes that involve activation of microglia and astrocytes contribute to the development of Gαi2 protein-dependent, salt-sensitive hypertension. • What is the main finding and its importance? The main finding is that PVN-specific inflammatory processes, driven by microglial activation, appear to be linked to the development of Gαi2 protein-dependent, salt-sensitive hypertension in Sprague-Dawley rats. This finding might reveal new mechanistic targets in the treatment of hypertension.

ABSTRACT

The central mechanisms underlying salt-sensitive hypertension, a significant public health issue, remain to be established. Researchers in our laboratory have reported that hypothalamic paraventricular nucleus (PVN) Gαi2 proteins mediate the sympathoinhibitory and normotensive responses to high sodium intake in salt-resistant rats. Given the recent evidence of central inflammation in animal models of hypertension, we hypothesized that PVN inflammation contributes to Gαi2 protein-dependent, salt-sensitive hypertension. Male Sprague-Dawley rats received chronic intracerebroventricular infusions of a targeted Gαi2 or control scrambled oligodeoxynucleotide (ODN) and were maintained for 7 days on a normal-salt (NS; 0.6% NaCl) or high-salt (HS; 4% NaCl) diet; in subgroups on HS, intracerebroventricular minocycline (microglial inhibitor) was co-infused with ODNs. Radiotelemetry was used in subgroups of rats to measure mean arterial pressure (MAP) chronically. In a separate group of rats, plasma noradrenaline, plasma renin activity, urinary angiotensinogen and mRNA levels of the PVN pro-inflammatory cytokines TNFα, IL-1β and IL-6 and the anti-inflammatory cytokine IL-10 were assessed. In additional groups, immunohistochemistry was performed for markers of PVN and subfornical organ microglial activation and cytokine levels and PVN astrocyte activation. High salt intake evoked salt-sensitive hypertension, increased plasma noradrenaline, PVN pro-inflammatory cytokine mRNA upregulation, anti-inflammatory cytokine mRNA downregulation and PVN-specific microglial activation in rats receiving a targeted Gαi2 but not scrambled ODN. Minocycline co-infusion significantly attenuated the increase in MAP and abolished the increase in plasma noradrenaline and inflammation in Gαi2 ODN-infused animals on HS. Our data suggest that central Gαi2 protein prevents microglial-mediated PVN inflammation and the development of salt-sensitive hypertension.

Authors+Show Affiliations

The Whitaker Cardiovascular Institute, Boston University, Boston, MA, USA. Department of Health Sciences, Boston University Sargent College, Boston, MA, USA.The Whitaker Cardiovascular Institute, Boston University, Boston, MA, USA. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.The Whitaker Cardiovascular Institute, Boston University, Boston, MA, USA. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.The Whitaker Cardiovascular Institute, Boston University, Boston, MA, USA. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.The Whitaker Cardiovascular Institute, Boston University, Boston, MA, USA. Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA, USA.The Whitaker Cardiovascular Institute, Boston University, Boston, MA, USA. Department of Health Sciences, Boston University Sargent College, Boston, MA, USA.Department of Anatomy & Neurobiology, Boston University School of Medicine, Boston, MA, USA.Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.The Whitaker Cardiovascular Institute, Boston University, Boston, MA, USA. Department of Health Sciences, Boston University Sargent College, Boston, MA, USA. Department of Pharmacology and Experimental Therapeutics, Boston University School of Medicine, Boston, MA, USA.

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31631436

Citation

Moreira, Jesse D., et al. "Inhibition of Microglial Activation in Rats Attenuates Paraventricular Nucleus Inflammation in Gαi2 Protein-dependent, Salt-sensitive Hypertension." Experimental Physiology, 2019.
Moreira JD, Chaudhary P, Frame AA, et al. Inhibition of microglial activation in rats attenuates paraventricular nucleus inflammation in Gαi2 protein-dependent, salt-sensitive hypertension. Exp Physiol. 2019.
Moreira, J. D., Chaudhary, P., Frame, A. A., Puleo, F., Nist, K. M., Abkin, E. A., ... Wainford, R. D. (2019). Inhibition of microglial activation in rats attenuates paraventricular nucleus inflammation in Gαi2 protein-dependent, salt-sensitive hypertension. Experimental Physiology, doi:10.1113/EP087924.
Moreira JD, et al. Inhibition of Microglial Activation in Rats Attenuates Paraventricular Nucleus Inflammation in Gαi2 Protein-dependent, Salt-sensitive Hypertension. Exp Physiol. 2019 Oct 20; PubMed PMID: 31631436.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Inhibition of microglial activation in rats attenuates paraventricular nucleus inflammation in Gαi2 protein-dependent, salt-sensitive hypertension. AU - Moreira,Jesse D, AU - Chaudhary,Parul, AU - Frame,Alissa A, AU - Puleo,Franco, AU - Nist,Kayla M, AU - Abkin,Eric A, AU - Moore,Tara L, AU - George,Jonique C, AU - Wainford,Richard D, Y1 - 2019/10/20/ PY - 2019/06/13/received PY - 2019/09/09/accepted PY - 2019/10/22/entrez KW - Gαi2 protein KW - neuroinflammation KW - salt-sensitive hypertension JF - Experimental physiology JO - Exp. Physiol. N2 - NEW FINDINGS: • What is the central question of this study? We hypothesized that central inflammatory processes that involve activation of microglia and astrocytes contribute to the development of Gαi2 protein-dependent, salt-sensitive hypertension. • What is the main finding and its importance? The main finding is that PVN-specific inflammatory processes, driven by microglial activation, appear to be linked to the development of Gαi2 protein-dependent, salt-sensitive hypertension in Sprague-Dawley rats. This finding might reveal new mechanistic targets in the treatment of hypertension. ABSTRACT: The central mechanisms underlying salt-sensitive hypertension, a significant public health issue, remain to be established. Researchers in our laboratory have reported that hypothalamic paraventricular nucleus (PVN) Gαi2 proteins mediate the sympathoinhibitory and normotensive responses to high sodium intake in salt-resistant rats. Given the recent evidence of central inflammation in animal models of hypertension, we hypothesized that PVN inflammation contributes to Gαi2 protein-dependent, salt-sensitive hypertension. Male Sprague-Dawley rats received chronic intracerebroventricular infusions of a targeted Gαi2 or control scrambled oligodeoxynucleotide (ODN) and were maintained for 7 days on a normal-salt (NS; 0.6% NaCl) or high-salt (HS; 4% NaCl) diet; in subgroups on HS, intracerebroventricular minocycline (microglial inhibitor) was co-infused with ODNs. Radiotelemetry was used in subgroups of rats to measure mean arterial pressure (MAP) chronically. In a separate group of rats, plasma noradrenaline, plasma renin activity, urinary angiotensinogen and mRNA levels of the PVN pro-inflammatory cytokines TNFα, IL-1β and IL-6 and the anti-inflammatory cytokine IL-10 were assessed. In additional groups, immunohistochemistry was performed for markers of PVN and subfornical organ microglial activation and cytokine levels and PVN astrocyte activation. High salt intake evoked salt-sensitive hypertension, increased plasma noradrenaline, PVN pro-inflammatory cytokine mRNA upregulation, anti-inflammatory cytokine mRNA downregulation and PVN-specific microglial activation in rats receiving a targeted Gαi2 but not scrambled ODN. Minocycline co-infusion significantly attenuated the increase in MAP and abolished the increase in plasma noradrenaline and inflammation in Gαi2 ODN-infused animals on HS. Our data suggest that central Gαi2 protein prevents microglial-mediated PVN inflammation and the development of salt-sensitive hypertension. SN - 1469-445X UR - https://www.unboundmedicine.com/medline/citation/31631436/Inhibition_of_microglial_activation_in_rats_attenuates_paraventricular_nucleus_inflammation_in_Gαi2_protein-dependent,_salt-sensitive_hypertension L2 - https://doi.org/10.1113/EP087924 DB - PRIME DP - Unbound Medicine ER -