• 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.