Progress in mechanistic and clinical translational research of endothelin A receptor antagonists in the treatment of diabetic kidney disease: a narrative review

Background: Diabetic kidney disease (DKD) remains a leading cause of end-stage renal disease worldwide. Despite advances in renin-angiotensin-aldosterone system (RAAS) inhibitors, sodium-glucose cotransporter 2 (SGLT2) inhibitors, and mineralocorticoid receptor antagonists (MRAs), substantial residual renal risk persists. Endothelin-1 (ET-1), primarily via endothelin A (ETA) receptor activation, plays a central role in glomerular injury, inflammation, and fibrosis. Methodology: This narrative review summarizes current evidence on the mechanistic basis and clinical translation of ETA receptor antagonists (ERAs) in DKD. Relevant preclinical and clinical studies were identified through structured literature searches of PubMed, Embase, and Web of Science, focusing on mechanistic insights, therapeutic efficacy, and safety profiles. Results: Preclinical studies across diabetic models (e.g., streptozotocin-induced and db/db mice) demonstrate that ETA antagonism reduces glomerular hypertension, preserves podocyte integrity, and attenuates inflammatory and fibrotic signaling pathways. In clinical settings, the SONAR trial showed that atrasentan significantly reduced the risk of renal events (hazard ratio ~0.65) and achieved approximately 30-40% reduction in urinary albumin-to-creatinine ratio (UACR) in selected responders. However, ERA therapy is associated with fluid retention and increased heart failure risk. Notably, a biomarker-guided enrichment strategy, based on early albuminuria response during a run-in phase, improved patient selection and benefit-risk balance. Conclusion: ETA receptor antagonists represent a promising mechanism-based adjunctive therapy for DKD. Their future role is likely to be integrated within combination regimens alongside SGLT2 inhibitors and MRAs, guided by biomarker-driven precision medicine approaches to optimize efficacy while minimizing adverse effects.