The Effects Of Different Immunosuppresants On CAN By Affecting The TGF-β And Smads Signal Pathway

Objective Some recent studies suggested that CsA and FK506 can up-regulate the expression of TGF -β, whereas MMF and rapamycin (RPM) can down-regulate it, but the mechanism is still unclear. This study is to investigate the effect of different immunosuppresants on CAN by affecting TGF -β and Smads signal pathway. Methods Vascular smooth muscle cells (VMSC) from rat aorta were incubated with different immunosuppresants (CsA 3μg/ml, FK506 1μg/ml, MMF 0.3μg/ml, RPM10μg/ml), respectively for 6 or 12 hours. The SD→Wistar rat accelerated kidney sclerosis model was performed following the procedure of Kamada with our modification. Before the transplantation, the kidney was preserved one hour in 0~4℃ heparin sodium chloride solution for reinforcement of the cold ischemic injury. The rats were divided into 6 groups (each group n=8): Group A, psudo-OP; Group B, blank control; Group C, CsA 6 mg/(kg.d); Group D, FK506 0.15mg/(kg.d); Group E, MMF 20mg/(kg.d); Group F, RPM 0.8 mg/(kg.d). The Scr level and pathological changes according to Banff Standards were observed at the 4th, 8th and 12th weeks post-transplantation. The immunohistochemistry andreal-time fluorescence quantitative polymerase chain reaction (FQ-PCR) wereused to comprehend localization and expression of TGF-β1 and Smad2, 7 inVMSC and in the transplant kidney.Results CsA and FK506 simultaneously stimulated the gene expressionand protein production of TGF-β1, smad2 and inhibited expression of smad7both in VSMC and in transplant kidney, whereas MMF and RPM coulddown-regulate the gene expression and protein production of TGF-β1, smad2and up-regulate expression of smad7. There is no significant differencebetween CsA group and FK506 group, as well as MMF group and RPMgroup.Conclusion Our study suggests that different immunosuppresants can affectTGF-β1 and Smads signal pathway in rat VSMC and kidney graft differently.CsA and FK506 can cause CAN, owning to up-regulate the expression ofSmad2, and down-regulate smad7 expression. MMF and RPM can prevent orinhibit the progression of CAN because of down-regulating expression ofsmad2, and increase smad7 production.