From the Division of Nephrology, Department of Medicine, Duke University and Durham VA Medical Centers, NC (X.L., N.P.R., J.R.P., J.R., Y.W., R.G., S.D.C.).
Department of Immunology, Duke University School of Medicine, Durham, NC (S.D.C.).
Hypertension. 2020 Jan;75(1):131-138. doi: 10.1161/HYPERTENSIONAHA.119.13667. Epub 2019 Dec 2.
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.
FLT3L（Fms 样酪氨酸激酶 3 配体）可刺激经典树突状细胞（DC）的发育。在此，我们验证了一个假说，即经典 DC 通过促进肾脏液体潴留来驱动血压升高。在缺乏肾脏内经典 DC 的 FLT3L 缺陷（FLT3L）小鼠中，基础状态下的平均动脉压与野生型（WT）相似，但在 4 周慢性 Ang II（血管紧张素 II）输注期间，其高血压反应减弱。在 FLT3L 小鼠中，肾脏中效应记忆 T 细胞的比例与 WT 相似。然而，在 Ang II 输注后，FLT3L 肾脏中的效应记忆 T 细胞比例明显低于 WT，表明在肾素-血管紧张素系统激活后，经典 DC 增强了效应 T 细胞在肾脏中的积聚。与较低的血压相一致，Ang II 输注的 FLT3L 小鼠的心脏肥大减轻，促高血压细胞因子的肾脏 mRNA 表达降低。此外，Ang II 输注的 FLT3L 小鼠的尿液中氧化应激标志物 8-异前列腺素的排泄量较低，肾脏 NADPH 氧化酶 2 的 mRNA 水平也较低。在 Ang II 输注第 7 天的腹腔盐水挑战试验中，FLT3L 小鼠比 WT 小鼠排泄更高比例的注射体积和钠。与这种增强的利尿作用一致，FLT3L 肾脏中氯化钠共转运蛋白和上皮钠通道的所有 3 个亚基的 mRNA 表达降低了 40%以上。因此，经典的 FLT3L 依赖性 DC 促进肾脏 T 细胞的激活，继而导致氧化应激、液体潴留和血压升高。
