Abstract P110: Classical Dendritic Cells Mediate Hypertension by Promoting Oxidative Stress and Renal Fluid Retention

Dendritic cells (DCs) promote hypertension via the activation of T cells, but the specific DC subtypes that mediate hypertension require elucidation. We previously found that Fms-like tyrosine kinase 3 ligand-deficient (FLT3L -/- ) mice that lack classical CD11c hi MHCII hi DCs have blunted renal accumulation of effector T cells vs wild-type (WT) mice during chronic angiotensin (Ang) II infusion (500ng/kg/min). In the current studies, we tested the hypothesis that classical DCs drive blood pressure elevation by promoting renal fluid and sodium retention. We found that FLT3L -/- mice had mean arterial pressures (MAPs) similar to WTs at baseline but had blunted hypertensive responses measured by radiotelemetry during 4 weeks of chronic Ang II infusion (166±2 vs.178±4 mmHg, p <0.02). Consistent with their lower blood pressures, the Ang II-infused FLT3L -/- mice had attenuated cardiac hypertrophy (6.7±0.1 vs. 7.8±0.4 mg/g body weight, p <0.01) and reduced renal mRNA expression for the pro-hypertensive cytokines IL-1β (0.4±0.1 vs. 1.0±0.2; p<0.02) and TNF-α (0.6±0.1 vs. 1.0±0.1; p<0.02). The Ang II-infused FLT3L -/- mice had lower urinary excretion of the oxidative stress marker 8-isoprostane (1403±158 vs. 2257±372 pg/24 hours; p<0.04). To examine the effects of classical DCs on renal fluid retention after 7 days of Ang II, we performed an IP saline challenge test. FLT3L -/- mice excreted higher proportions of the injected volume (69±7 vs. 49±5%; p<0.04) and sodium (54±7 vs. 38±4%; p=0.07) compared to WTs. Consistent with this enhanced diuresis, mRNA expression for the NCC sodium transporter and all 3 subunits of ENaC were diminished by > 40% (0.4 of 1) in FLT3L -/- kidneys compared to the WTs during hypertension. Thus, classical FLT3L + DCs promote renal T cell activation with consequent oxidative stress, fluid retention, and blood pressure elevation.