Effect of angiotensin-converting enzyme inhibition on growth factor mRNA in chronic renal allograft rejection in the rat

Background. Despite considerable progress in immunosuppression, the inciden ce of chronic renal allograft rejection has not decreased. Recent studies h ave revealed that angiotensin-converting enzyme (ACE) inhibition ameliorate s graft arteriosclerosis. glomerulosclerosis and tubular atrophy. Moreover. it decreases systemic and glomerular capillary hydrostatic pressure in a r at kidney allograft model. We evaluated the effects of the ACE inhibitor en alapril on cytokine and growth factor expression in chronically rejecting r at kidney allografts. Methods. Kidneys of Fisher (F344) rats were orthotopically transplanted int o Lewis (Lew) rats. To prevent acute rejection. cyclosporine A (1.5 mg/kg/d ay) was given to all recipients during the first 10 days after transplantat ion. Enalapril (60 mg/L) or vehicle was added to the drinking water 10 days after transplantation. Animals were harvested 20 weeks after transplantati on for histologic and immunohistologic studies, as well as for evaluation o f cytokine and growth factor mRNA by semiquantitative polymerase chain reac tion. Results. Controls developed severe signs of chronic rejection. such as glom erular and vascular lesions, associated with a large number of infiltrating leukocytes. Enalapril-treated animals developed less proteinuria and other signs of chronic rejection. The mRNA levels of transforming growth factor- beta(1) (TGF-beta(1)), platelet-derived growth factor A and B chain (PDGF A and B), insulin-like growth factor-I (IGF-I). interleukin-1 (IL-1), and mo nocyte chemoattractant protein-1 (MCP-1) were significantly reduced in the enalapril group and were most pronounced for IL-1 and PDGF A. In addition. we found an increased level of renal angiotensinogen mRNA after treatment w ith enalapril. Conclusions. Treatment with enalapril attenuated the development of protein uria. ameliorated morphological damage, decreased leukocyte infiltration. a nd prevented a rise in renal mRNA levels of growth factors and cytokines in kidney grafts in a rat model of chronic renal allograft rejection.