Abstract
Afferent arteriolopathy is the most characteristic lesion of chronic cyclosporine (CsA) nephrotoxicity. We investigated the effect of therapeutic doses of mycophenolate mofetil (MMF) in a model of chronic CsA nephrotoxicity where transforming growth factor-β (TGF-β) was shown to play a central role. Rats treated with vehicle, MMF 10 mg/kg/day, CsA 10 mg/kg/day or CsA + MMF were sacrificed at 7 or 28 days. Physiologic and histologic changes were studied in addition to TGF-β1 mRNA and protein expressions, and mRNA expression of plasminogen activator inhibitor-1 (PAI-1) and the extracellular matrix (ECM) proteins biglycan and types I and IV collagen. While MMF markedly ameliorated afferent arteriolopathy, it had no significant effect on interstitial fibrosis and tubular atrophy. In addition, MMF treatment reduced both TGF-β1 mRNA and protein levels by 39% and 32%, respectively (p < 0.05 vs. CsA only). The expression of the ECM proteins followed that of TGF-β1 and was significantly decreased with MMF; a similar effect was observed with PAI-1, suggesting an increase in ECM degradation. These results suggest that MMF exerts a beneficial effect on CsA arteriolopathy and that it decreases TGF-β1. While this drug combination may be useful clinically, long-term studies are needed to determine if MMF has a lasting benefit.
Original language | English (US) |
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Pages (from-to) | 1550-1559 |
Number of pages | 10 |
Journal | American Journal of Transplantation |
Volume | 3 |
Issue number | 12 |
DOIs | |
State | Published - Dec 2003 |
Externally published | Yes |
Keywords
- Arteriolopathy
- Biglycan
- Chronic nephrotoxicity
- Collagen
- Cyclosporine
- Extracellular matrix
- Fibrosis
- Mycophenolate mofetil
- Plasminogen activator inhibitor-1
- Rats
- Transforming growth factor-β1
ASJC Scopus subject areas
- Immunology and Allergy
- Transplantation
- Pharmacology (medical)