Dendritic cell-specific SMAD3, downstream of JAK2, contributes to inflammation and salt-sensitivity of blood pressure

Abstract Salt-sensitivity of blood pressure (SSBP), characterized by acute changes in blood pressure with changes in dietary sodium intake, is an independent risk factor for cardiovascular disease and mortality in people with and without hypertension. We previously found that elevated sodium concentration activates antigen presenting cells (APCs), resulting in high blood pressure, but the mechanisms are not known. Here, we hypothesized that APC-specific JAK2 expression contributes to SSBP. We performed bulk or single-cell transcriptomic analyses following in vitro monocytes exposed to high salt, and in vivo high sodium treatment in humans using a rigorous salt-loading/depletion protocol to phenotype SSBP after a two week anti-hypertensive drug washout period. Here we found that expression of the genes of the JAK2 pathway mirrored changes in blood pressure after salt-loading and depletion in salt-sensitive but not salt-resistant humans. Ablation of JAK2, specifically in CD11C + APCs, attenuated salt-induced hypertension in mice with SSBP. Mechanistically, we found that SMAD3 acts downstream of JAK2 and STAT3, leading to increased production of highly reactive isolevuglandins and pro-inflammatory cytokine IL-6 in renal APCs, which activate T cells. This results in the production of IL-17A, IL-6, and TNF-⍺. Our findings reveal APC JAK2 signaling as a potential target for the treatment of SSBP.