Combination therapy with sirolimus and mycophenolate mofetil: effects on the kidney and on transforming growth factor-??11

Sirolimus (SRL) is not nephrotoxic, but it has been shown to increase transforming growth factor (TGF)-beta. We investigated the effect of combining mycophenolate mofetil (MMF) with SRL on renal structure and function and on TGF-beta1. Rats treated with vehicle (VH), MMF 10 mg/kg/d, SRL 0.3 mg/kg/d, or SRL+MMF were killed at 28 days. The physiologic and histologic changes and expression of TGF-beta1, plasminogen activator inhibitor-1, and extracellular matrix proteins were studied. Although SRL alone did not alter renal function and structure, it increased TGF-beta1 mRNA by 44% and protein by 48% (P <0.05 vs. VH). Treatment with MMF did not affect TGF-beta1. When combined with SRL, MMF decreased TGF-beta1 expression to VH levels. A similar trend was observed with plasminogen activator inhibitor-1 and extracellular matrix proteins. The long-term consequence of increased TGF-beta in SRL-treated kidneys remains unknown. However, because MMF can reverse this trend, SRL and MMF combination therapy may be protective.