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Endothelin antagonists and renal protection.
A Benigni1, N Perico, G Remuzzi
1Mario Negri Institute for Pharmacological Research, Ospedali Riuniti di Bergamo, Italy.
Journal of Cardiovascular Pharmacology
|September 8, 2000
Summary
Proteinuric nephropathies cause kidney damage. Endothelin-1 (ET-1) produced by tubular cells contributes to this injury, but ET receptor antagonists show renoprotective effects in preclinical models.
Area of Science:
- Nephrology
- Molecular Biology
- Pharmacology
Background:
- Proteinuric nephropathies, including diabetic kidney disease, lead to progressive renal damage.
- Excessive protein reabsorption by tubular cells upregulates growth factors and inflammatory mediators.
- Renal tubular cells synthesize endothelins (ETs), potent vasoconstrictors and mitogens, with ET-1 synthesis increasing upon protein overload.
Purpose of the Study:
- To investigate the role of endothelin-1 (ET-1) in proteinuric kidney disease.
- To evaluate the therapeutic potential of endothelin receptor antagonists in preclinical models of progressive renal disease.
Main Methods:
- Studies in animal models of proteinuric nephropathies (e.g., remnant kidney, experimental diabetes, lupus nephritis).
- Measurement of renal ET-1 gene expression and urinary ET-1 excretion.
- Administration of selective and non-selective ET receptor antagonists (peptide and non-peptide).
Main Results:
- Increased renal ET-1 synthesis and urinary excretion correlate with proteinuria and renal damage in vivo.
- ET receptor antagonists demonstrated renoprotective effects in various animal models of progressive renal disease.
- Peptide-based ET antagonists may have limitations for human use.
Conclusions:
- Endothelin-1 is implicated as a mediator of renal injury in proteinuric nephropathies.
- ET receptor antagonists show promise for treating proteinuric kidney diseases.
- Non-peptide ET receptor antagonists may offer a viable therapeutic strategy for patients unresponsive to current treatments.