R Gao1, Y Lu, Y P Xin, X H Zhang, J Wang, Y P Li. 1. Transplantation Institute, West China Hospital, Sichuan University, Guoxuexiang 37, Chengdu, China 610041.
Abstract
OBJECTIVE: This study investigated the effects of various immunosuppressants on chronic allograft nephropathy (CAN) by affecting transforming growth factor-beta (TGF-beta) and Smads signal pathway. METHODS: Vascular smooth muscle cells (VMSC) from rat aorta were incubated for 6 or 12 hours with various immunosuppressants. Cyclosporine (CsA) (3 microg/mL), FK506 (1 microg/mL), mycophenolate mofetil (MMF) (0.3 microg/mL), rapamycine (Rapa) (10 microg/mL), CsA (1 microg/mL/MMF 0.3 microg/mL). We used the Sprague-Dawley Wistar rat accelerated kidney sclerosis model. Before transplantation, the kidney was preserved 1 hour in 0 degrees C to 4 degrees C heparin sodium chloride solution to reinforce the cold ischemia injury. The rats were divided into eight groups (each group n = 8): group A, pseudo-OP; group B, isotransplantation; group C, CsA 6 mg/kg . d; group D, FK506 0.15 mg/kg . d; group E, MMF 20 mg/kg . d; group F, Rapa 0.8 mg/kg. d; group G, CsA 3 mg/kg . d + MMF 20 mg/kg . d. The serum creatinine levels and pathological changes, according to the Banff scheme, were observed at 2, 4, 6, 8 and 12 weeks posttransplantation. Immunohistochemistry and quantitative fluorescence polymerase chain reactions were used to end localize and quantitate the expression of TGF-beta1 and Smad 2, 3, 7 in VMSC and in the transplanted kidney. RESULTS: CsA and FK506 stimulated gene expression and protein production of TGF-beta1, smad2, and smad3, but inhibited expression of smad7 both in VSMC and in the transplanted kidney. In contrast, MMF and Rapa down-regulated gene expression and protein production of TGF-beta1, smad2, 3 while up-regulating expression of smad7. There was no significant difference between the CsA group and the FK506 group, as well as the MMF group and the Rapa group. The group treated with CsA + MMF was similar to the MMF and the Rapa groups. CONCLUSION: Our study suggested that various immunosuppressants affected differentially TGF-beta1 and Smads signal pathways in rat VSMC and kidney grafts. CsA and FK506 can cause CAN, owing to up-regulated expression of smad2 and smad3, and down-regulation of smad7 expression. MMF and Rapa can prevent the CAN progression, because of down-regulation of the expression of smad2 and smad3, with increased smad7 production.
OBJECTIVE: This study investigated the effects of various immunosuppressants on chronic allograft nephropathy (CAN) by affecting transforming growth factor-beta (TGF-beta) and Smads signal pathway. METHODS: Vascular smooth muscle cells (VMSC) from rat aorta were incubated for 6 or 12 hours with various immunosuppressants. Cyclosporine (CsA) (3 microg/mL), FK506 (1 microg/mL), mycophenolate mofetil (MMF) (0.3 microg/mL), rapamycine (Rapa) (10 microg/mL), CsA (1 microg/mL/MMF 0.3 microg/mL). We used the Sprague-Dawley Wistar rat accelerated kidney sclerosis model. Before transplantation, the kidney was preserved 1 hour in 0 degrees C to 4 degrees C heparin sodium chloride solution to reinforce the cold ischemia injury. The rats were divided into eight groups (each group n = 8): group A, pseudo-OP; group B, isotransplantation; group C, CsA 6 mg/kg . d; group D, FK506 0.15 mg/kg . d; group E, MMF 20 mg/kg . d; group F, Rapa 0.8 mg/kg. d; group G, CsA 3 mg/kg . d + MMF 20 mg/kg . d. The serum creatinine levels and pathological changes, according to the Banff scheme, were observed at 2, 4, 6, 8 and 12 weeks posttransplantation. Immunohistochemistry and quantitative fluorescence polymerase chain reactions were used to end localize and quantitate the expression of TGF-beta1 and Smad 2, 3, 7 in VMSC and in the transplanted kidney. RESULTS:CsA and FK506 stimulated gene expression and protein production of TGF-beta1, smad2, and smad3, but inhibited expression of smad7 both in VSMC and in the transplanted kidney. In contrast, MMF and Rapa down-regulated gene expression and protein production of TGF-beta1, smad2, 3 while up-regulating expression of smad7. There was no significant difference between the CsA group and the FK506 group, as well as the MMF group and the Rapa group. The group treated with CsA + MMF was similar to the MMF and the Rapa groups. CONCLUSION: Our study suggested that various immunosuppressants affected differentially TGF-beta1 and Smads signal pathways in rat VSMC and kidney grafts. CsA and FK506 can cause CAN, owing to up-regulated expression of smad2 and smad3, and down-regulation of smad7 expression. MMF and Rapa can prevent the CAN progression, because of down-regulation of the expression of smad2 and smad3, with increased smad7 production.
Authors: Kyu Ha Huh; Hyung Joon Ahn; Jehyun Park; Man Ki Ju; Jae Sook Song; Myoung Soo Kim; Soon Il Kim; Yu Seun Kim Journal: Pediatr Nephrol Date: 2008-12-18 Impact factor: 3.714
Authors: Balarka Banerjee; Michael Musk; Erika N Sutanto; Stephanie T Yerkovich; Peter Hopkins; Darryl A Knight; Suzanna Lindsey-Temple; Stephen M Stick; Anthony Kicic; Daniel C Chambers Journal: PLoS One Date: 2012-12-21 Impact factor: 3.240