Endothelin Signaling in Chronic Kidney Disease

Endothelin-1 (ET-1) is a potent vasoactive peptide that plays a central role in the pathogenesis and progression of chronic kidney disease (CKD). Under normal conditions, balanced activation of ETA and ETB receptors regulates vascular tone, glomerular filtration and tubular salt handling. In CKD, excessive ET-1 production—driven by hyperglycaemia, hypertension and inflammation—shifts this balance towards ETA receptor-mediated vasoconstriction, mesangial proliferation and extracellular matrix deposition, while ETB-mediated clearance and vasodilatory pathways are overwhelmed. The result is sustained glomerular hypertension, proteinuria and tubulointerstitial fibrosis. Therapeutic strategies targeting the endothelin axis, particularly selective ETA receptor antagonists, have demonstrated promise in reducing albuminuria, preserving estimated glomerular filtration rate (eGFR) and attenuating renal fibrosis. Emerging insights into microRNA-mediated regulation, receptor isoform selectivity and combination approaches with renin-angiotensin and sodium-glucose cotransporter 2 inhibitors are informing next-generation interventions.

Research from Nature Portfolio

Foundational work has uncovered that ETA receptor antagonism can modulate epigenetic regulators to protect renal tubular cells. In experimental models of diabetic nephropathy, blockade of ET-1 signalling reduced histone modifications at microRNA promoters, leading to upregulation of the anti-ageing factor klotho. This mechanism preserved tubular integrity and reduced apoptosis under hyperglycaemic stress. Such insights into the cross-talk between endothelin signalling and microRNA networks highlight novel molecular targets for CKD therapy.

Endothelin Signaling in Chronic Kidney Disease publication trend

The graph below shows the total number of articles in endothelin signaling in chronic kidney disease across all publications each year (not limited to Nature Index journals).

Technical terms

Endothelin-1 (ET-1): 21-amino acid peptide that is a potent vasoconstrictor and pro-fibrotic mediator in the cardiovascular and renal systems.

ETA receptor: G-protein-coupled receptor subtype that mediates vasoconstriction, mesangial proliferation and fibrotic signalling upon ET-1 binding.

ETB receptor: G-protein-coupled receptor subtype that facilitates vasodilation, clearance of ET-1 and natriuresis when activated.

Endothelin receptor antagonist (ERA): Pharmacological inhibitor of ETA and/or ETB receptors used to reduce albuminuria and slow CKD progression.

Albuminuria: Pathological presence of albumin in urine reflecting glomerular barrier damage and a risk factor for CKD progression.

eGFR: Estimated glomerular filtration rate, a clinical measure of kidney filtration capacity and function.

References

1. Insulin resistance, kidney outcomes and effects of the endothelin receptor antagonist atrasentan in patients with type 2 diabetes and chronic kidney disease. Cardiovascular Diabetology (2023).
2. Post hoc analysis of the SONAR trial indicates that the endothelin receptor antagonist atrasentan is associated with less pain in patients with type 2 diabetes and chronic kidney disease. Kidney International (2023).
3. Atrasentan increased the expression of klotho by mediating miR-199b-5p and prevented renal tubular injury in diabetic nephropathy. Scientific Reports (2016).
4. Endothelin Receptor Antagonists in Kidney Disease. International Journal of Molecular Sciences (2023).
5. Endothelin-1 Increases Collagen Accumulation in Renal Mesangial Cells by Stimulating a Chemokine and Cytokine Autocrine Signaling Loop*. Journal of Biological Chemistry (2010).