1. What is Endothelin-1 (ET-1)?

Endothelin-1 (ET-1) is one of the most potent vasoconstrictors in the body, primarily produced by endothelial cells, podocytes, and tubular cells in the kidney. ET-1 binds to endothelin A (ETA) receptors and endothelin B (ETB) receptors, playing a crucial role in chronic kidney disease (CKD) and IgA nephropathy. Overactivation of ETA receptors accelerates kidney damage, making them a key target for novel therapies.

2. Pathophysiology of Endothelin-1 in IgA Nephropathy

(1) Overview of IgA Nephropathy

IgA nephropathy is the most common primary glomerular disease, characterized by abnormal immune responses leading to IgA immune complex deposition in the glomerulus, causing chronic inflammation and fibrosis. In this process, ET-1 expression is upregulated, exacerbating kidney damage.

(2) Pathological Effects of ET-1 in IgA Nephropathy

✅ Glomerular Injury and Increased Proteinuria

• ET-1 binding to ETA receptors damages glomerular endothelial cells and podocytes, leading to increased protein permeability and proteinuria.
• Glomerular hemodynamic changes: ET-1 induces vasoconstriction, increasing glomerular capillary pressure and accelerating damage.

✅ Inflammation Promotion

• ET-1 stimulates pro-inflammatory cytokines (TNF-α, IL-6, etc.) in glomerular and tubular cells.
• Increased cytokine production attracts immune cells (macrophages, monocytes), sustaining chronic inflammation.

✅ Fibrosis Induction

• ET-1 activates TGF-β (Transforming Growth Factor-β) signaling, promoting glomerular and tubular fibrosis.
• Increased collagen synthesis in the tubulointerstitial area accelerates kidney sclerosis.

3. Causes of Increased Endothelin-1 Expression in Chronic Kidney Disease (CKD)

In CKD, inflammation, hypertension, oxidative stress, and renal hypoxia drive ET-1 overexpression, worsening kidney dysfunction.

(1) Inflammation and Immune Activation

• Glomerular and tubular cell injury triggers TNF-α, IL-6, TGF-β release.
• TGF-β further stimulates ET-1 expression, perpetuating fibrosis.

(2) Hypertension and Hemodynamic Changes

• Glomerular hypertension due to CKD increases endothelial ET-1 secretion.
• Renin-angiotensin-aldosterone system (RAAS) activation elevates angiotensin II (Ang II) levels, which in turn induces ET-1 production.

(3) Oxidative Stress

• In CKD, reactive oxygen species (ROS) levels rise, activating ET-1 gene transcription.
• NF-κB transcription factors enhance ET-1 synthesis, worsening inflammation.

(4) Renal Hypoxia

• Chronic kidney ischemia activates HIF-1α (hypoxia-inducible factor-1α), directly increasing ET-1 gene transcription.

4. Therapeutic Effects of ETA Receptor Blockers (Atrasentan)

ETA receptor antagonists prevent ET-1 from binding to ETA receptors, offering several therapeutic benefits.

✅ Reduction of Proteinuria

• Restores glomerular permeability, reducing proteinuria.

✅ Inhibition of Inflammation

• Lowers inflammatory cytokine secretion, decreasing immune cell infiltration.

✅ Prevention of Fibrosis

• Blocks TGF-β signaling, preventing kidney fibrosis progression.

✅ Stabilization of Hemodynamics

• Helps regulate intrarenal blood pressure, preventing further glomerular injury.

5. Latest Research: Atrasentan in Clinical Trials

ALIGN Clinical Trial (NEJM, 2025)

A recent study published in The New England Journal of Medicine (NEJM) reported that the ETA receptor blocker Atrasentan significantly reduced proteinuria in patients with IgA nephropathy.

🔹 Study Overview

• Participants: 340 IgA nephropathy patients (proteinuria ≥1g/day, eGFR ≥30 ml/min/1.73m²)
• Groups: Atrasentan (0.75mg/day) vs. placebo
• Study duration: 36 weeks
• Primary outcome: Change in 24-hour urine protein-to-creatinine ratio

🔹 Key Findings

• Atrasentan group: 38.1% reduction in proteinuria
• Placebo group: 3.1% reduction
• Difference: -36.1% (P<0.001)

🔹 Safety Profile

• Adverse event rates were similar between the Atrasentan (82.2%) and placebo (84.7%) groups.
• Common side effects: Nasopharyngitis, peripheral edema, anemia (no reported heart failure cases).

6. Conclusion

In IgA nephropathy, ET-1 plays a key role in glomerular injury, inflammation, and fibrosis, driving disease progression. ETA receptor blockers like Atrasentan show promising therapeutic potential by reducing proteinuria and protecting kidney function. Recent clinical trial results highlight its efficacy and safety, warranting further research into its long-term benefits in CKD management.

7. References

1. Heerspink, H. J. L., et al. “Atrasentan in Patients with IgA Nephropathy.” N Engl J Med, 2025;392:544-554.
2. Kohan, D. E., & Barton, M. “Endothelin and endothelin antagonists in chronic kidney disease.” Kidney Int, 2014;86:896-904.
3. Wyatt, R. J., & Julian, B. A. “IgA nephropathy.” N Engl J Med, 2013;368:2402-2414.

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