Targeting vascular and macrophage endothelin-1 signaling for the treatment of salt-sensitive hypertension

Activation of vascular endothelial cells (ECs), smooth muscle cells (SMCs), and macrophages contributes to the development of salt-sensitive (SS) hypertension (HTN), a condition that poses significant clinical challenges due to its association with drug resistance (DR), leading to higher mortality. SS/DR HTN is characterized by elevated plasma endothelin-1 (ET-1) levels, which drive renal inflammation, fibrosis, and subsequent kidney dysfunction. Activation of ECs, SMCs and macrophages by high salt and ET-1 triggers the production of reactive oxygen species (ROS), ET-1, and inflammatory cytokines, thereby promoting salt retention, kidney dysfunction, and sustained HTN. Here, we report for the first time that indole-3 acetic acid (IAA) profoundly reduces blood pressure (BP) elevation in Dahl salt-sensitive (DSS) hypertensive rats via a novel dual-action mechanism, which involves antagonism of endothelin receptors (ET A R and ET B R) and inhibition of endothelin-converting enzyme-1 (ECE-1). Using unbiased ligand-based in silico screening, we identified three IAA analogs (IAAA1–3) with high potential for interaction with ET targets, including ET A R, ET B R, and ECE-1. Functional assays reveal that IAA and its analogs reverse ET-1-induced vasoconstriction in resistance mesenteric arteries (RMAs) and inhibit ET-1-evoked global Ca 2+ release in ETR-expressing cells. Among these, IAA and IAAA2 exhibit the highest efficacy against ET A R with minimal inhibition of ET B R. Given that macrophages express ETRs and ECE-1 and contributes to the overall elevated pool of ET-1 to drive SS HTN and kidney dysfunction, we hypothesized that IAA and its analogs could inhibit macrophage activation and suppress cytokine and ET-1 production. Indeed, our data confirm that IAA and its analogs (IAAA1–3) inhibit macrophage activation, highlighting their therapeutic potential for treating SS HTN and kidney dysfunction. This novel dual-targeted approach inhibiting both vascular and macrophage endothelin systems represents a promising strategy for addressing inflammation-driven SS HTN and its associated renal complications. American Heart Association This abstract was presented at the American Physiology Summit 2025 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.