Abstract P616: Renal Sympathetic Outflow And Beta-adrenergic Signaling Promote Dendritic Cell Activation In Hypertension
Hypertension is associated with increased sympathetic outflow and activation of adaptive immunity. In hypertensive states, proteins that are oxidatively modified by highly reactive γ-ketoaldehydes (isoketals) accumulate in dendritic cells (DCs). These isoketal-protein adducts are immunogenic and lead to subsequent activation of T cells. We hypothesized that renal sympathetic nerves link the central nervous system to immune activation in hypertension. To test this, we performed bilateral renal denervation (RDN) in C57BL/6 mice by applying phenol to the renal artery. One week later, mice received an subcutaneous infusion of angiotensin II (490 ng/kg/min) for 14 days. RDN lowered the hypertensive response to angiotensin II infusion (130±3 vs. 161±3 mmHg) as measured by telemetry. By flow cytometry, we found that RDN reduced accumulation of T cells in the kidney. Ang II infusion caused resulted in 15-25% increases in expression of the maturation markers CD80 and CD86, as well as 2-fold increase in isoketal adducts in the DCs of spleen. It also increased IL-1α, IL-1β, and IL-6 production by splenic DCs by 4 to 6-fold. These increases were attenuated by RDN. Having confirmed that DCs express almost every subtype of adrenergic receptor by real time PCR, we further determined if sympathetic neurotransmitters contribute to DC activation by treating bone marrow-derived DCs with either norepinephrine (NE) or neuropeptide Y (NPY) in vitro. As measured by flow cytometry, NE dose-dependently increased isoketal-protein adducts in DCs (vehicle: 19 ± 3 vs. 3 μmol/L: 39 ± 4%). This was prevented by pretreating cells with the β-adrenergic antagonist propranolol (1 μmol/L), but not by blocking α1 or α2 adrenoreceptors with prazosin and yohimbine. In contrast, NPY did not affect DC isoketal-protein content. Therefore, our data indicate that renal sympathetic nerves increase isoketal-adduct formation in DCs via β-adrenergic signaling and that this contributes to the activation of adaptive immunity in hypertension. These data suggest that beta blockade might have previously unappreciated anti-inflammatory effects in the treatment of hypertension.
Author Disclosures: L. Xiao: None. A. Kirabo: None. R. Loperena: None. J.D. Foss: None. R. Mernaugh: None. L. Roberts: None. H.A. Itani: None. W. Chen: None. D.G. Harrison: None.
- © 2015 by American Heart Association, Inc.