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Effects of cyclosporin A on the synthesis, excretion, and metabolism of endothelin in the rat
- Source :
- Scopus-Elsevier
-
Abstract
- Abstract Increasing evidence suggests that endothelin, a potent vasoconstrictor, is implicated in cyclosporin A (CsA)–induced nephrotoxicity. Increased levels of urinary and circulating endothelin have been described in CsA-treated humans and animals. The exact mechanisms by which CsA induces these increases are still unknown, and no data indicate whether these elevated levels reflect increased synthesis or decreased clearance of endothelin. In the present study, we investigated the effects of CsA administration (50 mg/kg per day IP for 6 days) to rats on plasma and urinary levels of endothelin; expression of endothelin-1 (ET-1), ET-3, and endothelin-converting enzyme in renal tissue; clearance of infused 125 I–ET-1; and degradation of 125 I–ET-1 by recombinant neutral endopeptidase. Rats given CsA for 6 days developed severe renal insufficiency, as shown by a 74% decrease in creatinine clearance rate (Ccr) ( P P P 125 I–ET-1 from the blood or the renal and pulmonary uptake of the peptide. Moreover, CsA did not affect the degradation of 125 I–ET-1 by highly purified recombinant neutral endopeptidase, a well-known endothelinase. Taken together, these data suggest that the elevated urinary endothelin levels obtained after CsA treatment originate from the kidney and reflect increased renal synthesis of ET-1. Moreover, the production of endothelin appears to be regulated at the mRNA transcription level, and expressions of ET-1 and ET-3 are regulated independently.
- Subjects :
- medicine.hormone
Male
medicine.medical_specialty
Molecular Sequence Data
Renal function
Biology
Endothelin-Converting Enzymes
Sulfonamide
Kidney
Endothelin
Nephrotoxicity
Endothelins
Rats, Sprague-Dawley
chemistry.chemical_compound
Internal medicine
Cyclosporin a
Metalloendopeptidase
Internal Medicine
medicine
Aspartic Acid Endopeptidase
Animals
Aspartic Acid Endopeptidases
Neprilysin
Creatinine
Sulfonamides
Base Sequence
Animal
Metalloendopeptidases
Bosentan
Recombinant Protein
Recombinant Proteins
Rats
Molecular Probe
medicine.anatomical_structure
Endocrinology
chemistry
Molecular Probes
Cyclosporine
Rat
Endothelin receptor
Subjects
Details
- Database :
- OpenAIRE
- Journal :
- Scopus-Elsevier
- Accession number :
- edsair.doi.dedup.....9e0386274ce0b82e69cccfcc81b51db5