Abstract 384: Activation of Microglia in Paraventricular Nucleus of Hypothalamus: A Source of Central Cytokines Induced by Nuclear Factor-kappa B or Oxidative Stress in Hypertension
Neurohumoral mechanisms play an important role in the pathophysiology of hypertension. Recent findings from our lab indicate that pro-inflammatory cytokines (PIC) and their nuclear transcription factor (NF-κB) are activated in the neurons of brain cardiovascular centers, thereby contributing to the development of hypertension. However, the role played by supporting cells in the brain, like microglia, is not known. In this study, we show that activated microglial cells also produce PIC and induce oxidative stress and contribute to the progression of hypertension. Rats were infused intravenously (i/v) with angiotensin II (ANG II, 0.6μg/hr) or saline for 4 weeks, while one group received pyrrolidine dithiocarbamate (PDTC, 5μg/hr), an inhibitor of NF-κB; or the NAD(P)H oxidase inhibitor, apocynin (APO, 60 μg/hr) via intracerebroventricular (ICV) cannula along with ANGII (i/v). In ANG II+vehicle rats, mean blood pressure (MAP) was increased on day 4 and remained elevated throughout the study. ANGII infused animals had increased activated microglia in the PVN, with increased TNF-α, IL-1β, gp91phox, and COX-2 staining in the PVN when compared with saline-infused rats. ANG II infused animals also had increased levels of TNF-α, IL-1β and PGE2 in the CSF and plasma. Furthermore, ANGII infused rats had increased renal sympathetic activity (RSNA) accompanied by increased plasma norepinphrine. In contrast, treatment with ANG II+PDTC or ANG II+APO resulted in fewer activated microglia, with decreased expression of TNF-α, IL-1β, gp91phox and COX-2 in the PVN. Treatments also decreased CSF and plasma concentrations of TNF-α, IL-1β, COX-2 and NE when compared to ANG II+vehicle group. These findings suggest that activated microglial cells increase PIC in the PVN and contribute to oxidative stress in an ANGII infusion model of hypertension. This increased superoxide perpetuates more NF-κB which in turn increases PIC, thereby contributing to the progression of hypertension.