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A total of 244 human renal biopsy cases were examined under the following three categories of renal disease: (i) transplanted kidney (TK; 127 cases); (ii) primary glomerular disease (GD; 88 cases); and (iii) others (29 cases). In these cases, the immunohistochemical distribution of apoptosis-related proteins (Fas antigen and bcl-2 protein) was investigated. Despite no detection in normal kidney tissues, Fas antigen was highly expressed in the tubular epithelium, indicating that Fas antigen expression was induced on the tubular epithelium in human renal disease. Furthermore, in TK Fas antigen expression was significantly frequent in acute rejection including acute rejection borderline (9/43 cases) and acute rejection stages I-III (10/28 cases), as compared with that in control cases (no rejection, 1/32 cases). Fragmented DNA stained with in situ nick end-labeling was predominantly detected in the tubular epithelium in 6 of 48 cases (23 with transplanted kidney and 21 with glomerular disease). Characteristic nuclear apoptotic changes were detected in the tubular epithelium by light microscopy. These results indicate that apoptosis takes place mainly in the renal tubular epithelium. The present experimental study revealed that Fas mRNA transcripts were induced in human renal cell line by interferon-γ. This suggests that in situ induction of Fas antigen in the tubular epithelium is mediated, at least in part, by cytokines in association with inflammatory lymphocytic infiltrates. It was also revealed that anti-Fas monoclonal antibody induced apoptosis of the renal cell line through stimulation with interferon-γ. Taken together, the results suggest that induced expression of Fas antigen on the tubular epithelium might play an important role in apoptosis under acute renal graft rejection.