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

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  Figure 1. The comprehensive pathogenesis of diabetic kidney disease (DKD) and the mechanistic targets of endothelin A (ETA) receptor antagonists. Metabolic disturbances, including hyperglycemia, insulin resistance, and adipose dysfunction, increase oxidative stress (ROS) and upregulate endothelin-1 (ET-1) production. ET-1 signaling via ETA receptors induces endothelial dysfunction (reduced nitric oxide bioavailability), mesangial expansion with extracellular matrix accumulation, and podocyte injury (foot process effacement, detachment, epithelial–mesenchymal transition, and apoptosis). These changes are accompanied by immune activation and release of pro-inflammatory cytokines (IL-6, TNF-α) and profibrotic mediators (TGF-β1, α-SMA, CTGF), promoting tubulointerstitial fibrosis. Collectively, these processes lead to albuminuria, glomerulosclerosis, and progressive renal dysfunction. Selective ETA receptor antagonists (e.g., atrasentan) mitigate these pathological pathways, while combination therapy with SGLT2 inhibitors provides additional renoprotective effects.

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  Figure 2. The endothelin-1–ETA axis as a central cardio–kidney–metabolic link in diabetic kidney disease. Metabolic dysregulation associated with diabetes and insulin resistance promotes ET-1 overproduction through hyperglycemia, hyperinsulinemia, adipose tissue inflammation, and skeletal muscle dysfunction. The kidney serves as the primary target organ, where ET-1–mediated ETA activation induces podocyte injury, mesangial expansion, glomerular hypertension, inflammation, and fibrosis. Selective ETA receptor antagonism attenuates renal injury while preserving ETB receptor–mediated protective effects. Combination therapy with sodium–glucose cotransporter 2 (SGLT2) inhibitors further reduces intraglomerular pressure, enhances natriuresis, and mitigates fluid retention, thereby integrating renal, cardiovascular, and metabolic protection.

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  Figure 3. Complementary mechanisms and clinical benefits of combined ETA receptor antagonism and SGLT2 inhibition. ETA receptor antagonists block ETA-mediated signaling in glomerular cells, reducing inflammation, fibrosis, and podocyte injury, but may induce distal tubular sodium retention as a side effect. SGLT2 inhibitors reduce proximal tubular sodium and glucose reabsorption, decrease glomerular hyperfiltration, alleviate tubular hypoxia, and promote osmotic diuresis. Together, combined ERA and SGLT2 inhibitor therapy enhances proteinuria reduction, preserves estimated glomerular filtration rate, and achieves a manageable safety profile through complementary and counter-regulatory mechanisms.