Abstract P182: Antigen Presenting Cell-specific Keap1-Nrf2 pathway Mediates Salt-Sensitive Hypertension in Humans

Abstract

Background: Hypertension remains the leading cause of mortality worldwide and is a primary risk factor for cardiovascular disease. Of the 1.3 billion people globally affected by hypertension, over 50% exhibit salt-sensitivity of blood pressure (SSBP), which leads to higher rates of mortality, morbidity, and kidney damage compared to those with salt-resistant hypertension. Previously our research has shown that high salt intake activates antigen-presenting cells (APCs), causing inflammation and hypertension. This pro-inflammatory response is partly driven by the epithelial sodium channel (ENaC), which facilitates sodium ion transport into APCs. While the Keap1-Nrf2 pathway is known for its role in antioxidant defense and inflammatory responses, its contribution to salt-sensitive hypertension remains unclear. We hypothesize that ENaC-dependent sodium entry triggers inflammation and activates the Sp1-MALAT1-Keap1-Nrf2 signaling axis in APCs, thereby contributing to SSBP. Method: We utilized a well-established inpatient protocol to phenotype participants for salt sensitivity of blood pressure. Additionally, we conducted RNA sequencing (RNAseq) on human monocytes exposed to elevated sodium levels in vitro and performed Cellular Indexing of Transcriptomes and Epitopes by Sequencing (CITE-seq) analysis on peripheral blood mononuclear cells (PBMCs). Results: We found that whereas high salt did not significantly increases expression of Sp1 (5380.63 ± 359.77 vs 7414.54 ± 434.19, q=0.829), MALAT1 (86888.54 ±12200.12 vs 219429.90 ± 109994.16, q=0.717), Keap1 (1586.54 ± 132.94 vs 2203.72 ± 177.48, q=0.884), it significantly increased Nrf2 expression (5080.36 ± 416.64 vs 5443.54 ± 432.78, q=0.019) in RNAseq analysis of human high salt compared to normal salt treated monocyte. Furthermore, the results of the CITE-seq experiment indicated that changes in the expression of the Sp1 correlate with SSBP (r=0.5205, p=0.038). Conclusion: These preliminary findings reveal a physiological link between inflammation and salt-sensitive hypertension through the Sp1-MALAT1-Keap1-Nrf2 signaling axis in APCs. The activation of APCs mediated by Sp1 could potentially serve as a diagnostic marker for salt sensitivity in blood pressure.