Abstract MP05: Pvn-specific Microgliosis And Inflammation Precedes Sympathoexcitation In gαI 2 Protein-dependent, Salt-sensitive Hypertension

Abstract

Aim: Hypothalamic paraventricular nucleus (PVN) Gαi 2 proteins mediate sympathoinhibitory responses to a high salt (HS; 4% NaCl) diet. Failure to upregulate Gαi 2 proteins in response to a HS diet results in PVN inflammation and salt sensitive hypertension (SSHTN). We hypothesize that microglial-mediated PVN inflammation precedes sympathoexcitation in Gαi 2 protein-dependent SSHTN. Methods: Three-month-old male Sprague Dawley rats implanted with ICV cannulas fitted to osmotic minipumps to centrally infuse either a control scrambled (SCR) oligodeoxynucleotide (ODN) or a Gαi 2 targeted ODN, which downregulates CNS Gαi 2 proteins by ~85%, (25μg/5μl/day/ODN) were placed on a 1-7-day normal salt (NS; 0.6% NaCl) or HS diet (n=5/group) and underwent cardiac perfusion. Brain immunohistochemistry was used to assess PVN and subfornical organ microgliosis and qualitatively assess levels of PVN pro-inflammatory cytokines (PIC) IL-1β, IL-6, and TNFα. In additional groups, MAP was assessed via radiotelemetry, and whole blood and kidneys were obtained for ELISA measurement of plasma and renal norepinephrine (NE) as estimates of sympathetic tone. Results: By 24h in control SCR ODN infused rats a HS diet, which did not alter MAP or microglial activation, evoked sympathoinhibition. In contrast, in Gαi 2 ODN infused rats a HS diet did not result in sympathoinhibition and evoked significant increases in MAP, PVN microgliosis and PVN PIC expression within 24h, and elevated renal NE content by Day 3. Conclusions: Our data suggest that in the male Sprague-Dawley model of PVN Gαi 2 protein-dependent SSHTN PVN inflammation (microgliosis and PIC production) precedes sympathoexcitation.