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.