Selective endothelin A receptor antagonism in chronic kidney disease: improving clinical application
Authors: Moedt Erik , Wasehuus Victor S , Heerspink Hiddo J L 
Published: September 2024

PLAIN ENGLISH SUMMARY

Endothelin-1 (ET-1) is a peptide that is involved in various chronic diseases including cardiovascular and kidney disease. ET-1 can bind to two receptors, endothelin A (ETA) and endothelin B (ETB), which are found in different organs and tissues. When ET-1 binds to the ETA receptor, it causes blood vessels to narrow, while binding of ET-1 to the ETB receptor causes blood vessels to widen. These receptors help regulate fluid and electrolyte balance in the kidneys, as well as the kidney's ability to filter various substances out of the body. Overactivation of ET-1 can occur in people with diabetes or obesity, which can damage the structure and function of the kidney.
Studies in mice and humans with kidney disease have shown that blocking the ETA receptor improves kidney health. As a result, medicines that specifically block the ETA receptor, known as endothelin receptor antagonists (ERAs), are a promising option for treating these kidney diseases. The first ERA (sparsentan) is now available for use in patients with immunoglobulin A (IgA) nephropathy, a specific type of kidney disease. It should be noted that ERAs can cause side effects. Fluid retention, which can increase the risk of heart failure, is a side effect that is particularly observed in patients with type 2 diabetes and severe kidney disease. This side effect is less often observed in patients with IgA nephropathy or patients without diabetes.
Treatment strategies to optimize safe and effective use of ETA blockers are being developed. Overall, these insights offer hope for better care of patients with kidney disease.

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.