Cytomegalovirus increases collagen synthesis in chronic rejection in the rat.

Abstract

We have demonstrated previously that cytomegalovirus (CMV) infection enhances chronic renal allograft rejection in a rat model. Interstitial fibrosis, a characteristic finding for chronic rejection, was also more prominent in CMV-infected grafts. The effect of CMV on the development of fibrosis in this model was investigated here at the molecular level. The collagen/DNA ratio, gene expression of type I and III collagen mRNAs and the presence of myofibroblasts were examined. Transplantations were performed under triple drug immunosuppression in a rat strain combination of DA(RT1(a)) and BN(RT1(n)). One group of animals was infected with rat CMV and the other was left uninfected. The grafts were harvested at different time points post-transplantation. Graft histology was evaluated according to the Banff criteria and quantified by the chronic allograft damage index (CADI). Total collagen was measured and DNA and RNA were extracted from the grafts. Type I and III collagen mRNAs were determined by slot blot and in situ hybridizations. Myofibroblasts were demonstrated by immunohistochemistry. The time-related increase of the collagen/DNA ratio in the CMV-infected grafts was higher than in the uninfected animals, correlating with the development of fibrosis at the histology. The expression of type I and III collagen mRNAs peaked shortly after transplantation, together with the presence of myofibroblasts, with significantly higher peaks in the CMV-infected grafts compared with the non-infected ones. CMV increases the expression of both type I and III collagens and the accumulation of myofibroblasts, and enhances total collagen synthesis in the development of interstitial fibrosis in chronic renal allograft rejection.