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

ABSTRACT: 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.

SUBMITTER: Lu X

PROVIDER: S-EPMC7004279 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Lu Xiaohan X Rudemiller Nathan P NP Privratsky Jamie R JR Ren Jiafa J Wen Yi Y Griffiths Robert R Crowley Steven D SD

Hypertension (Dallas, Tex. : 1979) 20191202 1

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<sup>-/-</sup>) 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<sup>-/-</sup> mice, th ...[more]

PMID: 31786985

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Project description:Cholinergic receptor activation leads to premature development of hypertension and infiltration of proinflammatory CD161a+/CD68+ M1 macrophages into the renal medulla. Renal inflammation is implicated in renal sodium retention and the development of hypertension. Renal denervation is known to decrease renal inflammation. The objective of this study was to determine the role of CD161a+/CD68+ macrophages and renal sympathetic nerves in cholinergic-hypertension and renal sodium retention. Bilateral renal nerve denervation (RND) and immune ablation of CD161a+ immune cells were performed in young prehypertensive spontaneously hypertensive rat (SHR) followed by infusion of either saline or nicotine (15 mg·kg-1·day-1) for 2 wk. Immune ablation was conducted by injection of unconjugated azide-free antibody targeting rat CD161a+. Blood pressure was monitored by tail cuff plethysmography. Tissues were harvested at the end of infusion. Nicotine induced premature hypertension, renal expression of the sodium-potassium chloride cotransporter (NKCC2), increases in renal sodium retention, and infiltration of CD161a+/CD68+ macrophages into the renal medulla. All of these effects were abrogated by RND and ablation of CD161a+ immune cells. Cholinergic activation of CD161a+ immune cells with nicotine leads to the premature development of hypertension in SHR. The effects of renal sympathetic nerves on chemotaxis of CD161a+ macrophages to the renal medulla, increased renal expression of NKCC2, and renal sodium retention contribute to cholinergic hypertension. The CD161a+ immune cells are necessary and essential for this prohypertensive nicotine-mediated inflammatory response.NEW & NOTEWORTHY This is the first study that describes a novel integrative physiological interaction between the adrenergic, cholinergic, and renal systems in the development of hypertension, describing data for the role of each in a genetic model of essential hypertension. Noteworthy findings include the prevention of nicotine-mediated hypertension following successful immune ablation of CD161a+ immune cells and the necessary role these cells play in the overexpression of the sodium-potassium-chloride cotransporter (NKCC2) in the renal medulla and renal sodium retention. Renal infiltration of these cells is demonstrated to be dependent on the presence of renal adrenergic innervation. These data offer a fertile ground of therapeutic potential for the treatment of hypertension as well as open the door for further investigation into the mechanism involved in inflammation-mediated renal sodium transporter expression. Taken together, these findings suggest immune therapy, renal denervation, and, possibly, other new molecular targets as having a potential role in the development and maintenance of essential hypertension.

Dataset Information

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

Publications

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

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