Adenovirus-mediated antisense-ERK2 gene therapy attenuates chronic allograft nephropathy

BACKGROUND: The aim of this study was to investigate the effects of adenovirus-mediated antisense ERK2 (Adanti-ERK2) gene therapy on chronic allograft nephropathy. METHODS: We employed a rat kidney transplantation mode (F344-->Lewis) and studied four groups: (1) controls (n = 6); (2) vector controls (n = 6); (3) an Adanti-ERK2 group (n = 10); and (4) an isograft group (n = 4). The animals were monitored for proteinuria, graft histology, infiltrating cells, and immune-related gene (interleukin-2 [IL-2] and intracellular adhesion molecule-1 [ICAM-1]) expression for 20 weeks after transplantation. RESULTS: The control group had increasing proteinuria during the 20-week follow-up. All rats showed advanced chronic renal failure associated with strong immune cell infiltration and immune gene expression. Chronic graft injury was accelerated in the vector-control group, but no significant difference was observed compared with the control group. In contrast, the Adanti-ERK2 group showed less inflammation and improved graft histology/function compared with controls. Moreover, ERK2 protein expression in the Adanti-ERK2 group was lower than in the control group (P < .05) and vector-control group (P < .05). Furthermore, serial estimates of genes (IL-2, ICAM-1) related to chronic rejection showed significant downregulation in the Adanti-ERK2 group (P < .01). CONCLUSIONS: Adenovirus-mediated antisense ERK2 gene therapy attenuated chronic allograft nephropathy. The protective effects of antisense ERK2 gene therapy may have derived from a blocked ERK signal transduction pathway, which reduced ERK expression as well as those of immune-related genes.