Hypertension as an Immune Disorder: From Cellular Drivers to Molecular Mediators

ABSTRACT Hypertension is a major global health burden, affecting nearly half of the adult population and contributing significantly to morbidity and mortality. While traditionally viewed through its hemodynamic effects, growing evidence implicates immune dysregulation as a central driver of hypertension and its associated end‐organ damage. Immune cells, including T cells, dendritic cells, and macrophages, infiltrate target organs and release mediators such as cytokines, reactive oxygen species, and metalloproteinases, promoting inflammation, fibrosis, and dysfunction. The discovery of isolevuglandin (IsoLG)‐adducted neoantigens has advanced our understanding of antigen‐dependent T cell activation in hypertension, revealing the roles of antigen‐presenting cells, immune memory, and co‐stimulatory pathways. Further, endothelial cells have emerged as non‐professional antigen‐presenting cells, orchestrating immune responses by modulating leukocyte recruitment and activation under mechanical and oxidative stress. Studies using experimental models and humans highlight the contributions of CD8 + T cells, immune memory formation, and altered sympathetic tone in perpetuating hypertension. Translational work has identified IsoLG‐adducted peptides and their processing by the immunoproteasome as critical mechanisms driving immune activation. Collectively, these findings underscore the interplay between the immune system and hypertension, offering novel therapeutic opportunities to target immune‐mediated mechanisms, mitigate blood pressure elevation, and reduce end‐organ damage. This review highlights these advances while recognizing the growing body of literature in this evolving field.