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

FLT3L (Fms-like tyrosine kinase 3 ligand) stimulates the development of classical dendritic cells (DCs). Here we tested the hypothesis that classical DCs drive blood pressure elevation by promoting renal fluid retention. FLT3L-deficient (FLT3L^-/-) mice that lack classical DCs in the kidney had mean arterial pressures similar to wild-types (WTs) at baseline but had blunted hypertensive responses during 4 weeks of chronic Ang II (angiotensin II) infusion. In FLT3L^-/- mice, the proportions of effector memory T cells in the kidney were similar to those in WTs at baseline. However, after Ang II infusion, proportions of effector memory T cells were dramatically lower in the FLT3L^-/- kidneys versus WTs, indicating that classical DCs augment the renal accumulation of effector T cells after renin-angiotensin system activation. Consistent with their lower blood pressures, the Ang II-infused FLT3L^-/- mice had attenuated cardiac hypertrophy and lower renal mRNA expression for pro-hypertensive cytokines. Moreover, the Ang II-infused FLT3L^-/- mice had lower urinary excretion of the oxidative stress marker 8-isoprostane and lower renal mRNA levels of nicotinamide adenine dinucleotide phosphate oxidase 2. In an intraperitoneal saline challenge test at day 7 of Ang II, FLT3L^-/- mice excreted higher proportions of the injected volume and sodium than WTs. Consistent with this enhanced diuresis, mRNA expressions for the sodium chloride cotransporter and all 3 subunits of the epithelial sodium channel were diminished by >40% in FLT3L^-/- kidneys compared with the WTs. Thus, classical FLT3L-dependent DCs promote renal T-cell activation with consequent oxidative stress, fluid retention, and blood pressure elevation.