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.

Sensory Afferent Renal Nerve Activated Gαi2 Subunit Proteins Mediate the Natriuretic, Sympathoinhibitory and Normotensive Responses to Peripheral Sodium Challenges

“…Several central sites, including the SFO and OVLT, (Larsen and Mikkelsen, 1995;Stocker et al, 2013;Simmonds et al, 2014) play an important role in mediating the actions of NaCl on blood pressure, in part through these areas' connections with the hypothalamic PVN, an integrative neural control center that modulates blood pressure and sympathetic outflow (Stocker et al, 2013;Fujita and Fujita, 2016). Our prior studies have shown a key role of central, and PVN specific, Gαi 2 proteins in influencing the cardiovascular, renal and sympathetic nervous system responses to acute challenges to sodium homeostasis and chronic elevations in dietary sodium intake (Figure 7; Kapusta et al, 2012Kapusta et al, , 2013Wainford et al, 2013;Moreira et al, 2019;Carmichael et al, 2020). However, the impact of central Gαi 2 proteins on the blood pressure responses to direct increases in central NaCl remain unknown.…”

“…Central Gαi 2 Oligodeoxynucleotide-Mediated Salt Sensitivity of Blood Pressure Occurs Independently of Brain Angiotensin II Type 1 Receptor Signal Transduction It is well established that activation of the brain AT1R evokes neurogenic hypertension. There is mounting evidence for several shared physiological responses across central AngII-mediated hypertension and our observation of Gαi 2 protein-dependent salt sensitive hypertension including neuroinflammation and increased sympathetic outflow (Shi et al, 2010;Wainford et al, 2013;Moreira et al, 2019;Carmichael et al, 2020;Mohammed et al, 2020). To investigate the potential interactions between centrally acting AngII and Gαi 2 subunit protein-gated pathways, we utilized pharmacological antagonism of the AT1R.…”

Apigenin Improves Hypertension and Cardiac Hypertrophy Through Modulating NADPH Oxidase-Dependent ROS Generation and Cytokines in Hypothalamic Paraventricular Nucleus

“…Chronic inflammation is involved in the progression of hypertension. Numerous studies from others and our laboratory demonstrated that proinflammatory cytokines produced in the PVN promote increase in blood pressure in various animal models of hypertension [14,43,44]. TNF-α overproduction or dysfunction, are closely related the development of chronic inflammatory diseases such as hypertension, via activating the nuclear factor-kappa B (NF-κB) [45].…”

The importance of bone marrow and the immune system in driving increases in blood pressure and sympathetic nerve activity in hypertension

“…Angiotensin II infusion results in increased microglial density in the PVN in rats, and inhibition of microglial activation by intracerebroventricular infusion of the anti‐inflammatory minocycline was found to reduce the Ang II‐induced microglial expansion and pro‐inflammatory cytokine production in the PVN, in addition to plasma NA, suggesting a reduction in SNA (Shi et al., 2010). Likewise, rats with salt‐sensitive HTN experienced an attenuation in microglial recruitment and activation after minocycline treatment (Moreira et al., 2019). Treatment of mice with s.c .…”