Immune Cell MK2 Drives Salt-Sensitive Hypertension and Kidney Injury

Hypertension has reached epidemic proportions in the United States, affecting nearly half the adult population. About 50% of hypertensive and 25% normotensive individuals exhibit salt-sensitivity of blood pressure (SSBP). SSBP, characterized by acute changes in BP in concert with changes in sodium intake, is an independent risk factor for cardiovascular disease. We and others have shown that inflammation and oxidative stress contribute to SSBP pathophysiology; however, the underlying molecular mechanisms remain poorly understood. Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2 or MK2) tightly regulates the production of proinflammatory cytokines and has been implicated in numerous inflammatory diseases. Based on the literature and our previous studies, we hypothesize that MK2, via STAT3, plays an essential role in SSBP pathophysiology and kidney injury. We performed CITE-Seq analyses in human PBMCs following a rigorous sodium salt-loading/depletion protocol to phenotype individuals for salt-sensitive hypertension. To complement CITE-Seq data, bulk RNA sequencing was performed on human monocytes cultured in high- or normal-sodium media. To study the mechanism, we used a whole-body MK2 knockout (MK2 D/D) mouse, measured BP with radiotelemetry, and performed flow cytometry for immunophenotyping and cytokine measurements following a high-salt diet. To confirm the role of APC-specific MK2, CD11c+ cells from wild-type (WT) mice were adoptively transferred into MK2 D/D mice, and BP was measured. To assess kidney excretory function, we performed a saline challenge experiment using metabolic cages. Our CITE-seq and Bulk-Seq data demonstrate that high salt upregulates MK2 expression (3978 vs. 6223 RPKM, p=0.003; bulk-seq). Transcriptomic data were validated in dendritic cells using flow cytometry (31039 vs. 53997 MFI; p=0.02, n=5) and Western blotting (1.45 vs. 2.96 protein density; p=0.03, n=6). Interestingly, our data indicate that MK2 expression in immune cells mirrors BP changes in salt-sensitive but not in salt-resistant patients. Correlation analysis suggests that MK2 gene expression positively correlates with pulse pressure (PP)(p=0.02, r=0.56). Higher PP indicates vascular dysfunction in humans. Pharmacological inhibition of MK2 attenuated p-STAT3 levels (1.2 vs 0.3; p=0.003, n=5), which was associated with reduced IL-6 (44.98 vs 34.93; p=0.02), TNF-α (7.2 vs 3.9; p=0.003), and IsoLG (50.02 vs 0.41.76; p=0.001) production in CD11c+ cells.MK2 D/D mice exhibit significantly lower BP than WT mice (110.6 vs. 91.97 MAP; p=0.003, n=4). Immunophenotyping of these mice showed reduced dendritic cell infiltration in the kidney (6455 vs. 3884 total count; p=04), which was associated with attenuated levels of p-STAT3 (31195 vs. 19059 MFI; p=0.03), TNF-α (1229 vs. 855.3; p=0.03), Nox2 (44086 vs. 32056; p=0.03), and IsoLGs (15441 vs. 10818; p=0.03) in MK2 D/D mice. Moreover, we found a significant reduction in TNF-α and IL-6 levels in renal CD4+ and CD8+ effector memory and central memory T cells. The renal response to volume load experiment demonstrated that kidney function in MK2 D/D was preserved after high-salt treatment (62 vs. 81%, p=0.04). The adoptive transfer experiment showed that CD11c+ cells from WT spleen, when injected intraperitoneally into MK2 D/D mice, restore BP, suggesting APC-specific MK2’s role in salt-sensitive hypertension. We are currently collecting data from CD11c-specific MK2 KO mice to further confirm the role of MK2 in SSBP pathophysiology. Our findings indicate that the MK2 plays an essential role in salt-sensitive hypertension and kidney injury and is a potential therapeutic target for diagnosing and treating SSBP in humans. This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.