Abstract 105: High Salt Activates Immune Cells to Promote Hypertension
High salt intake and inflammation are implicated in the genesis of hypertension. We have previously shown that hypertension activates dendritic cells (DCs), by promoting the formation of immunogenic isoketal-protein adducts. Recently it has become clear that sodium can accumulate in the interstitial space and promote inflammation. We hypothesized that high salt activates antigen presenting cells including monocytes and DCs to produce immunogenic isoketals. Exposure of mouse splenic DCs to high salt (190 mM) for 24 hours led to an increase in superoxide production compared to regular RPMI media (146.3±9.5 vs. 100.0±5.0 % control, p<0.001). This was NADPH oxidase dependent because incubation with the gp91ds-tat peptide prevented this effect. High salt exposure also led to an increase in the activation markers CD80, CD86, and a 48% increase in DCs containing isoketal-protein adducts. Moreover, DCs exposed to high salt drove T cell proliferation (5198.2±2398.6 vs. 15.3±7.1 proliferated CD4+ cells and 25381.6±9495.6 vs. 9.8±4.1 proliferated CD8+ cells, p<0.05). This was not due to increased osmolality, as mannitol did not mimic these effects. Western blots of protein extracts from DCs indicated that all NADPH subunits (p47phox, p22phox, gp91phox and p67phox) were increased by exposure of cells to high salt, and that these effects were prevented by inhibition of the salt-sensing glucokinase (SGK1). In additional studies, we found that human monocytes, which are precursors of myeloid DCs, from hypertensive subjects possess higher CD86 and isoketal-protein adducts compared to normotensives, and that these are further increased by exposure to 190 mM salt for 48 hours. Taken together, our data indicate that antigen presenting cells are activated by exposure to the high sodium environment that can occur in pro-hypertensive states, and that this likely involves increased expression and activation of the NADPH oxidase. Our data also describe a previously undefined role of the SGK1 in this process.
Author Disclosures: A. Kirabo: None. N.R. Barbaro: None. J.D. Foss: None. A.E. Norlander: None. S. Dikalov: None. M.S. Madhur: None. D.G. Harrison: None.
This research has received full or partial funding support from the American Heart Association, Greater Southeast Affiliate (Alabama, Florida, Georgia, Louisiana, Mississippi, Puerto Rico & Tennessee).
- © 2015 by American Heart Association, Inc.