Contribution of androgens to chronic allograft nephropathy is mediated by dihydrotestosterone

Background. Donor and recipient gender influence long-term allograft outcome after kidney transplantation. Sex hormones are likely to contribute to these gender-related differences. The present study investigated the role of androgens and their inhibition on the development of chronic allograft nephropathy. Methods. Male or female Fisher (F344) kidneys were orthotopically transplanted into intact male Lewis recipients. Animals were treated either with testosterone, the antiandrogen flutamide, the 5α-reductase inhibitor finasteride, or vehicle. Twenty weeks after transplantation animals were harvested for histology, immunohistology, and molecular analysis. Results. Testosterone treatment resulted in an increased proteinuria as well as profound glomerulosclerosis, tubulointerstitial fibrosis, and mononuclear cell infiltration that paralleled enhanced intragraft mRNA levels of transforming growth factor-β (TGF-β) and platelet-derived growth factor-A and -B chain (PDGF-A and -B). In contrast, flutamide and finasteride reduced glomerulosclerosis as well as the inflammatory cell infiltration associated with decreased TGF-β, PDGF-A, and -B chain mRNA expression. No gender-related donor differences were noted between the groups. Conclusions. Our data suggest that dihydrotestosterone mediates the adverse effects of androgens on chronic allograft nephropathy. The inhibition of androgens improves long-term allograft outcome after kidney transplantation.