Emerging roles for endothelial mineralocorticoid receptor in disease pathogenesis: potential new indications for mineralocorticoid receptor antagonism

Endothelial cell mineralocorticoid receptor (EC-MR) is a central regulator of vascular dysfunction beyond its classical renal role. This review summarizes recent advances in our understanding of how EC-MR disrupts vasomotor control via endothelial sodium channel activation, endothelial nitric oxide synthase dysregulation, and glycocalyx injury, amplifies inflammation and oxidative stress via serum and glucocorticoid-induced protein kinases-1, NLRP3, and mitochondrial reactive oxygen species, and drives fibrosis and remodeling via transforming growth factor-β (TGF-β). Through these mechanisms, EC-MR contributes to diabetes- and obesity-related vascular disease, acute and chronic kidney injury, and to new disorders, including ocular, skin, and hypoxic pulmonary diseases, reproductive vascular physiology, cerebrovascular dysfunction, COVID-19 vasculopathy, and cardiac dysfunction. Evidence from preclinical and clinical studies supports both traditional and novel nonsteroidal mineralocorticoid receptor antagonists as potential therapies for these additional indications and suggests endothelial biomarkers to guide translation.