Contribution of androgens to chronic allograft nephropathy is mediated by dihydrotestosterone

Background. Donor and recipient gender influence long-term allograft outcom e after kidney transplantation. Sex hormones are likely to contribute to th ese gender-related differences. The present study investigated the role of androgens and their inhibition on the development of chronic allograft neph ropathy. Methods. Male or female Fisher (F344) kidneys were orthotopically transplan ted into intact male Lewis recipients. Animals were treated either with tes tosterone, the antiandrogen flutamide, the 5 alpha -reductase inhibitor fin asteride, or vehicle. Twenty weeks after transplantation animals were harve sted for histology, immunohistology, and molecular analysis. Results. Testosterone treatment resulted in an increased proteinuria as wel l as profound glomerulosclerosis, tubulointerstitial fibrosis, and mononucl ear cell infiltration that paralleled enhanced intragraft mRNA levels of tr ansforming growth factor-beta (TGF-beta) and platelet-derived growth factor -A and -B chain (PDGF-A and -B). In contrast, flutamide and finasteride red uced glomerulosclerosis as well as the inflammatory cell infiltration assoc iated with decreased TGF-beta, PDGF-A, and -B chain mRNA expression. No gen der-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 a ndrogens improves long-term allograft outcome after kidney transplantation.