The many cell types of the kidney, precisely arranged, allow this organ to perform its complex physiologic functions. However, this architectural complexity makes gene transfer into the kidney difficult. One approach to delivering a therapeutic protein to the kidney is to transfer a gene to a non-renal tissue. Release of the protein into the circulation might then result in deposition in the kidney, if the protein has the appropriate molecular properties. In this study, we found that parenterally administered replication deficient adenovirus carrying the beta-galactosidase gene resulted in intense beta-galactosidase gene expression in hepatocytes. As a result of immune attack on transduced hepatocytes, beta-galactosidase protein from these cells is released into the circulation, transported, and deposited almost exclusively in kidney glomeruli. Intense beta-galactosidase activity was noted in both kidneys with a peak at two weeks following viral administration, concurrent with loss of beta-galactosidase positive hepatocytes. Consistent with our hypothesis of protein transfer, no beta-galactosidase mRNA was detected in glomeruli. Moreover, systemically administered protein generated similar glomerular beta-galactosidase activity. Finally, co-administration of murine CTLA4 Ig, an immunomodulator of T cell activation, with the adenovirus protected infected hepatocytes and markedly diminished glomerular beta-galactosidase activity. Collectively, these findings suggest that a therapeutic protein can be "targeted" to the renal glomerulus, utilizing the liver as a gene transfer organ.