MK2 Drives Salt-Sensitive Hypertension via Immunomodulatory Mechanism

Background: Salt-sensitivity of blood pressure (SSBP), characterized by acute changes in blood pressure in concert 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 activates antigen-presenting cells (APCs), resulting in high blood pressure, but the mechanisms are unknown. Here, we hypothesized that APC-specific MK2 through STAT3 contributes to SSBP. Methods: 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. We also used a whole-body MK2 knockout mouse and measured blood pressure with radiotelemetry after L-NAME and a high salt diet regimen. We employed flow cytometry for immunophenotyping and measuring cytokine levels. Results: We found high salt upregulates gene expression of the MAPK pathway while downregulating inhibitors of this pathway, such as SOCS and CISH, in human monocytes. Moreover, our data demonstrate that MK2 expression in APCs mirrors the changes in BP in salt-sensitive but not in salt-resistant patients after salt-load and depletion protocol. The transcriptomic expression of MK2 was validated using flow cytometry and Western blot, showing that high salt increases MK2 activation (phosphorylation of MK2). Additionally, pharmacological inhibition of MK2 attenuated STAT3 activation in APCs, which was associated with reduced IL-6, TNF-alpha, and IsoLG production. Whole-body MK2 KO mice exhibit attenuated hypertension in mice treated with high salt (n=4, each group). Immunophenotyping of these mice showed attenuated p-STAT3, TNF-alpha, and IL-6 production in the aorta and kidney. Conclusion: Our findings indicate the APC MK2 signaling pathway as a potential target for diagnosing and treating SSBP in humans. Funding: Other NIH Support - NHLBISBP in WT and MK2 KO mice