Combination therapy with sirolimus and mycophenolate mofetil: effects on the kidney and on transforming growth factor-beta1.
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.
Shihab
Fuad S
FS
Division of Nephrology, University of Utah School of Medicine, Salt Lake City, Utah, USA. Faud.Shihab@hsc.utah.edu
Bennett
William M
WM
Yi
Hong
H
Choi
Seung-Ok
SO
Andoh
Takeshi F
TF
D000818:Animals; D004359:Drug Therapy, Combination; D016326:Extracellular Matrix Proteins / Q000378:metabolism; D015870:Gene Expression / Q000187:drug effects; D007166:Immunosuppressive Agents / Q000494:pharmacology*; D007668:Kidney / Q000187:drug effects* / Q000502:physiology; D009173:Mycophenolic Acid / Q000031:analogs & derivatives* / Q000494:pharmacology*; D017395:Plasminogen Activator Inhibitor 1 / Q000235:genetics; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017207:Rats, Sprague-Dawley; D020123:Sirolimus / Q000494:pharmacology*; D016212:Transforming Growth Factor beta / Q000235:genetics*; D053773:Transforming Growth Factor beta1
D016326:Extracellular Matrix Proteins; D007166:Immunosuppressive Agents; D017395:Plasminogen Activator Inhibitor 1; D012333:RNA, Messenger; C508962:Tgfb1 protein, rat; D016212:Transforming Growth Factor beta; D053773:Transforming Growth Factor beta1; D009173:Mycophenolic Acid; D020123:Sirolimus