Abstract 17594: Brain Microglial Cytokines are Critical for Renin-Angiotensin-Aldoterone-System(RAAS)-Induced Neurogenic Hypertension
Purpose: Our previous studies have established that activation of microglial cells and production of proinflammatory cytokines (PIC) within the PVN are two critical events in the establishment of chronic angiotensin (Ang) II-induced neurogenic hypertension. These have led us to hypothesize that brain microglial cells are a primary target of Ang II, initiating a sequence of cellular and physiological events resulting in sympathetic nervous system activation and hypertension.
Methods: Microglial cells from the hypothalamus of Sprague-Dawley rats were established in primary culture. Their phenotype was confirmed by the presence of IBa1 immunoreactivity and high levels of CD11b mRNA, markers for microglia. They were used to determine the effects of, Ang II, prorenin and aldosterone (ALDO) on cytokine production. Neurogenic hypertensive mice were generated using decoxycorticosterone acetate (DOCA)-salt model (DOCA 50 mg s.c., 0.15 M NaCl in drinking water for 3 weeks). The PVN was dissected to determine PIC expression at the end of the protocol.
Results: Treatment of cultures with Ang II (100 nM) or ALDO (1 nM) for 24 hr increased the expression of PIC mRNAs, e.g. for tumor necrosis factor (TNF)α. Ang II and ALDO elicited respective 2- and 3-fold increases (P<0.05). More strikingly, we found that prorenin (20 nM, 24 hr) elicited highly significant 300- and 400-fold increases in the expression of TNFα and interleukin (IL)-1β mRNAs, respectively (P<0.05). These effects of prorenin were associated with respective 16- and 14-fold increases in NFκb1 and NFκbia mRNA levels, which are two subunits of the transcription factor NFκb complex. We previously demonstrated that DOCA mice exhibit a similar hypertensive phenotype as double transgenic hypertensive sRA mice, which display increased levels of PIC and activation of microglia in the PVN. Consistently, DOCA-salt mice exhibit respective 1.5, 1.08 and 1.09 fold increases in the expression of mRNAs for IL-1β, TNFα and IL-6 in the PVN compared to control mice (n=3-4).
Conclusion: These data indicate that brain microglial cells are the primary target of RAAS components in promoting PIC production, which in turn contribute to hypertension development.
- © 2011 by American Heart Association, Inc.