Endothelin System Activation via Autoantibodies in Lupus-Associated Hypertension

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by autoantibody production and systemic IgG deposition contributing to hypertension (HTN) and vascular dysfunction. The mechanistic cause of vascular complications in SLE is poorly understood. The endothelin (ET system), including endothelin-1 (ET-1) and endothelin receptor A and B (ET A R and ET B R), are critical for the development of vascular dysfunction. However, the mechanism by which autoantibodies targeting ET A R and ET B R contribute to endothelial dysfunction in SLE remains unknown. We hypothesized autoantibodies targeting ET A R and ET B R contribute to endothelial dysfunction in SLE and its associated HTN in human subjects. Utilizing two independent clinical cohorts (n=214), we quantified ET A R and ET B R autoantibodies (ET A R-, ET B R-AAs) and markers of endothelial activation soluble vascular adhesion molecule-1 (sVCAM-1) and intracellular adhesion molecule-1 (sICAM-1). We determined the functional relevance of ET A R- and ET B R-AAs using primary human renal endothelial cells (HRECs) stimulated with IgG isolated from SLE and control (HC) plasma. ET A R-AAs, ET B R-AAs, and sVCAM-1 were elevated in SLE subjects relative to non-SLE controls (p<0.0001 for all), which persisted regardless of the subject HTN status. ET A R-AAs were positively correlated with systolic (r=0.17, p =0.024) and diastolic blood pressure (r=0.19, p =0.011), sVCAM-1 (r=0.36, p <0.0001), sICAM-1 (r=0.21, p =0.006), and ET B R-AAs (r=0.63, p <0.0001). Principal component analysis (PCA) identified systolic blood pressure (0.647; PC1), sVCAM-1 (-0.576; PC2), and ET A R-AAs (0.531; PC3) significantly contributed to the variance between disease groups. Functionally, HRECs stimulated with SLE-derived IgG had increased ET-1 secretion compared to HC-IgG ( p =0.022). Blockade of ET A R (BQ123) reduced ET-1 secretion in HRECs treated with SLE-IgG ( p =0.006). In contrast, blockade of ET B R (BQ788) reduced ET-1 secretion in SLE-IgG (p=0.006) and HC-IgG ( p =0.027) treated cells. Live confocal calcium imaging of HRECs with IgG stimulation diminished the calcium flux in SLE-IgG ( p =0.012) during ET system blockade (BQ123 + BQ788) but not in HC-IgG-treated cells. These findings identify a novel autoantibody-mediated mechanism of endothelial activation and ET-1 dysregulation in SLE. Elevated ET A R- and ET B R-AAs present potential mechanistic drivers and biomarkers of vascular pathology in SLE-associated HTN.