FK506, transforming growth factor-β1 and mesangial matrix synthesis: Parallels and differences compared with cyclosporine A

Abstract

Cyclosporine A (CsA)-induced glomerulosclerosis is a well-described side effect of CsA treatment. Current evidence indicates that FK506 causes similar morphologic changes. Recently, we demonstrated that CsA up-regulates the expression of transforming growth factor-β1 (TGF-β1), its receptors type I (TβR-I) and type II (TβR-II), as well as related matrix protein synthesis in mesangial cells (MCs). Here, we assessed the effect of FK506 on the expression of TGF-β1, TβR-I, TβR-II, fibronectin (FN) and plasminogen activator inhibitor type-1 (PAI-1) in MCs. Resting MCs were incubated with/without FK506. Time- and concentration-dependent expression was measured at the mRNA and protein level. Compared to untreated controls, FK506 stimulated TGF-β1 mRNA (maximum at 8 h, 100 ng/mL: 2.13 ± 0.15-fold, P < 0.005) and protein expression (maximum at 96 h, 100 ng/mL: 1.96 ± 0.29-fold, P < 0.005). In contrast, TβR-I and TβR-II protein expression remained unchanged. Concerning matrix protein synthesis, FK506 slightly increased FN production (96 h, 100 ng/mL: 1.38 ± 0.28-fold, P < 0.05), but not PAI-1 production. These results indicate that, comparable to CsA, FK506 induced glomerulosclerosis is also due to a direct effect on mesangial matrix production, which is at least in part mediated via up-regulation of TGF-β1 expression. The fact that, unlike CsA, FK506 does not increase the expression of TβR-I, TβR-II, and PAI-1, deserves further investigation.