Mycophenolate mofetil ameliorates arteriolopathy and decreases transforming growth factor-beta1 in chronic cyclosporine nephrotoxicity.
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-beta (TGF-beta) 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-beta1 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-beta1 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-beta1 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-beta1. While this drug combination may be useful clinically, long-term studies are needed to determine if MMF has a lasting benefit.
Shihab
Fuad S
FS
Division of Nephrology, University of Utah School of Medicine, Salt Lake City, USA. Fuad.Shihab@hsc.utah.edu
Bennett
William M
WM
Yi
Hong
H
Choi
Seung Ok
SO
Andoh
Takeshi F
TF
D000818:Animals; D001158:Arteries / Q000187:drug effects* / Q000473:pathology; D016572:Cyclosporine / Q000633:toxicity*; D016326:Extracellular Matrix Proteins / Q000096:biosynthesis / Q000235:genetics; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects / Q000473:pathology; D007674:Kidney Diseases / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000096:biosynthesis / Q000235:genetics; D051381:Rats; D016212:Transforming Growth Factor beta / Q000187:drug effects*
D016326:Extracellular Matrix Proteins; D007166:Immunosuppressive Agents; D017395:Plasminogen Activator Inhibitor 1; D016212:Transforming Growth Factor beta; D016572:Cyclosporine; D009173:Mycophenolic Acid