Tuesday, May 7, 2024
5/7/2024
Project Abstract The goal of this proposed project titled “Sympathetic Activation of Renal Dendritic Cells during Hypertension” is to investigate the role of renal dendritic cell (rDC) adrenergic receptor (AR) activation in mediating cytokine-induced increases in sodium (Na) transporter activity and blood pressure (BP). Increased sympathetic nervous system (SNS) activity is known to play a role in hypertension (HTN). Additionally, there is an accepted role for inflammation in the pathogenesis of HTN. However, there is little data linking all these physiological mechanisms in salt-sensitive HTN. DCs cells secrete interleukin 6 (IL-6) producing a pro-inflammatory milieu. Our preliminary data show that rDCs are necessary for salt-sensitive HTN (SS-HTN) and intra-renal IL-6 levels. Using RNAseq analysis of whole kidney homogenates, we observed a change in the enrichment/Reactome pathway regulating AR expression and signaling mechanisms. These changes were observed in mice lacking rDCs, suggesting a role for AR in SS-HTN. Our robust in vivo data suggest that IL-6 infusion increases phosphorylated (pT53) NCC and ENaC activity. We also show that IL-6, plus high salt (HS, 4%), increases BP after 3 days following an immediate (day 1) reduction in urinary Na and total urinary volume. Together, these data strongly support a role for rDC- mediating local IL-6 levels, IL-6 increasing Na transporter expression and/or activity as well as Na-dependent BP. In this proposal, we hypothesize that SNS-mediated AR activation on rDCs increases intrarenal IL-6 levels, activating distal tubular Na transporters and increasing blood pressure. We will investigate this using an immortalized DC line (DC2.5), as well as freshly isolated rDCs. We will use radiotelemetry and mice lacking renal DCs in a norepinephrine infusion model of HTN, as well as renal denervation during SS-HTN. These in vivo studies will show dependence on rDCs for sympathetically-mediated HTN and renal innervation for renal IL-6.
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