Circulation research · 2026
Myeloid Activator Protein-1 Complex Contributes to Salt-Sensitive Hypertension.
СтатьяНазвание и аннотация: Перевод в очереди
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Ahmad Taseer, Saleem Mohammad, Mutchler Ashley Pitzer, Ertuglu Lale A, Sheng Quanhu, Albritton Claude F, Haynes Alexandria Porcia, Demirci Mert, Desta Selam, Khan Mohd Mabood, McMillan Ronald, Afolabi Jeremiah, Kirabo Annet
Аннотация
BACKGROUND: Salt-sensitivity of blood pressure is an independent risk factor for cardiovascular diseases, yet the molecular pathways linking dietary sodium to immune activation and hypertension remain poorly defined. We previously demonstrated that sodium entry into antigen-presenting cells via the ENaC (epithelial sodium channel) promotes inflammation and salt-sensitivity of blood pressure. AP-1 (activator protein-1; c-FOS, FOSB, c-JUN, JUNB, JUND) regulates inflammatory signaling, but its role in salt-sensitivity of blood pressure has not been elucidated. We hypothesized that high salt drives AP-1-mediated inflammatory activation in antigen-presenting cells, contributing to immune dysfunction and hypertension.
METHODS: Using SV129 salt-sensitive mice, we assessed blood pressure responses and profiled immune cell phenotypes under normal- and high-salt conditions by flow cytometry. RNA-seq was performed on human monocytes exposed to high salt in vitro. In a clinical study, we enrolled prehypertensive subjects and performed an inpatient salt-loading/depletion protocol to characterize AP-1 gene expression signatures in salt-sensitive versus salt-resistant individuals. To test causality, we adoptively transferred PBMCs from salt-sensitive, salt-resistant, and salt-sensitive individuals pretreated with T5224 (a selective AP-1 inhibitor) into immunodeficient NSG-(KbDb)null (IA)null humanized mice, followed by assessment of blood pressure, vascular reactivity, kidney function, and immune infiltration.
RESULTS: High salt robustly induced AP-1 gene expression in murine monocytes. In humans, salt-sensitive but not salt-resistant subjects exhibited concordant increases in AP-1 gene expression and blood pressure during salt loading. PBMCs from salt-sensitive individuals promoted greater tissue infiltration, AP-1 activation, and immune-mediated renal and vascular dysfunction in humanized mice compared with PBMCs from salt-resistant individuals. Strikingly, pretreatment of salt-sensitive PBMCs with T5224 abrogated these effects, preserving normal renal and vascular function despite high-salt exposure.
CONCLUSIONS: These findings identify AP-1 as a key transcriptional driver linking dietary sodium, immune activation, and salt-sensitivity of blood pressure. Targeting AP-1 signaling mitigates immune-mediated renal and vascular injury, highlighting a novel mechanistic pathway and a therapeutic target for salt-sensitive hypertension.
METHODS: Using SV129 salt-sensitive mice, we assessed blood pressure responses and profiled immune cell phenotypes under normal- and high-salt conditions by flow cytometry. RNA-seq was performed on human monocytes exposed to high salt in vitro. In a clinical study, we enrolled prehypertensive subjects and performed an inpatient salt-loading/depletion protocol to characterize AP-1 gene expression signatures in salt-sensitive versus salt-resistant individuals. To test causality, we adoptively transferred PBMCs from salt-sensitive, salt-resistant, and salt-sensitive individuals pretreated with T5224 (a selective AP-1 inhibitor) into immunodeficient NSG-(KbDb)null (IA)null humanized mice, followed by assessment of blood pressure, vascular reactivity, kidney function, and immune infiltration.
RESULTS: High salt robustly induced AP-1 gene expression in murine monocytes. In humans, salt-sensitive but not salt-resistant subjects exhibited concordant increases in AP-1 gene expression and blood pressure during salt loading. PBMCs from salt-sensitive individuals promoted greater tissue infiltration, AP-1 activation, and immune-mediated renal and vascular dysfunction in humanized mice compared with PBMCs from salt-resistant individuals. Strikingly, pretreatment of salt-sensitive PBMCs with T5224 abrogated these effects, preserving normal renal and vascular function despite high-salt exposure.
CONCLUSIONS: These findings identify AP-1 as a key transcriptional driver linking dietary sodium, immune activation, and salt-sensitivity of blood pressure. Targeting AP-1 signaling mitigates immune-mediated renal and vascular injury, highlighting a novel mechanistic pathway and a therapeutic target for salt-sensitive hypertension.