Expression of transforming growth factor-beta1 and hypoxia-inducible factor-1alpha in an experimental model of kidney transplantation.

Abstract

Ischemia-reperfusion syndrome has been recognized as an important pathogenic factor in renal transplantation, not only in the development of delayed graft function but also in the development of acute and chronic rejection. Hypoxia-inducible factor (HIF)-1 activates transcription of several genes implicated in cell survival, such as vascular endothelial growth factor (VEGF), and in tissue repair transforming growth factor (TGF)-beta. The purpose of this study was to characterize TGF-beta1, VEGF, and HIF-1alpha expression profiles during renal transplantation with heart-beating donors (HBD) and non-heart-beating donors (NHBD). An experimental model of renal transplantation using 40 pairs of large, white, Landrace pigs and including HBD and NHBD was used. Cold-ischemia time was the same in all groups (6 hr), and three groups of NHBD (30, 45, and 90 min) were studied. Immunosuppressive therapy consisted of cyclosporine, except in one HBD group, which was treated with azathioprine. TGF-beta1, VEGF, and HIF-1alpha expression profiles were performed in renal biopsies obtained at different times: after anesthetic induction (basal); 30, 45, and 90 min after warm ischemia; after cold ischemia; 1 hr after reperfusion; and 5 days after transplantation. TGF-beta1 expression increased after cold ischemia in HBD and remained unaltered during the surgical process in all NHBD groups. HIF-1alpha and VEGF expression were not greatly modified during surgery in the HBD or NHBD groups. All groups showed a significant increase in TGF-beta1 and HIF-1alpha expression as well as down-regulation of VEGF 5 days after transplantation, and these effects were independent of immunosuppressive treatment. There were no statistically significant differences among the groups at 5 days after transplantation, although the increase in TGF-beta1 was more pronounced in the HBD groups, especially in azathioprine-treated animals. The initial up-regulation of TGF-beta1 observed in HBD immediately after cold ischemia could have a positive effect on epithelial-tubular regeneration. Warm ischemia has a detrimental effect on TGF-beta1 expression during the early phases of renal transplantation and has no effect on VEGF and HIF-1alpha expression. The up-regulation of TGF-beta1 and HIF-1alpha observed after transplantation could have a positive effect on tubular repair. TGF-beta1 expression was lower in animals treated with cyclosporine, probably because of cellular toxicity.