Selective Endothelin A Receptor Antagonism in Chronic Kidney Disease: Improving Clinical Application

Abstract: Endothelin-1 (ET-1) is a 21-amino acid peptide involved in numerous cardiovascular and renal processes. ET-1 can bind to endothelin receptor A (ETA) and endothelin receptor B (ETB), which are found in various organs and tissues. In general, binding of ET-1 to the ETA receptor causes vasoconstriction, whereas activation of the ETB receptor leads to vasodilation. In the kidney, endothelin receptors regulate fluid and electrolyte balance, regional blood flow and glomerular filtration rate. In pathological conditions, ET-1 promotes kidney injury through adverse effects on the endothelial glycocalyx, podocytes and mesangial cells, and stimulating inflammation and fibrosis in the tubules. In experimental and clinical studies, inhibition of the ETA receptor has been shown beneficial in a variety of kidney diseases. These include diabetic kidney disease, immunoglobulin A nephropathy, focal segmental glomerulosclerosis and Alport syndrome. Accordingly, selective ETA endothelin receptor antagonists (ERA) may prove a viable therapeutic option in these diseases. However, clinical application is challenged by the occurrence of fluid retention which can lead to heart failure, in particular in patients with severe CKD. Concomitant use of sodium-glucose cotransporter 2 inhibitors (SGLT2i) may mitigate these adverse effects through their diuretic actions. The development of highly selective ETA antagonists, such as atrasentan and zibotentan, and the opportunities of combining these with SGLT2i, holds promise to optimize efficacy and safety of ERAs in clinical practice.