AIMS: The renin-angiotensin system (RAS) has been implicated in renal fibrosis through activation of the type I angiotensin II (Ang II) receptor (AT1R). Whether the other predominant Ang II receptor, the type 2 Ang II receptor (AT2R), has a fibrotic or sparing role in adult human renal tissue is unknown. MATERIALS AND METHODS: We used the reverse-transcription polymerase chain reaction (RT-PCR) to assess intragraft AT2R mRNA expression in biopsy samples from 23 renal transplant recipients. Potential correlations between intragraft AT2R mRNA. matrix-modulating genes and histologic evidence of chronic rejection were assessed. RESULTS: AT2R mRNA was confirmed by sequence analysis of the RT-PCR product. AT2R mRNA expression directly correlated with angiotensinogen (Spearman correlation coefficient (r(s)) 0.72; p = 0.0011) mRNA expression, and interestingly, AT2R mRNA inversely correlated with inflammatory gene expression in the biopsy samples. However, AT2R mRNA directly correlated with transforming growth factor-beta (TGF-beta) (r(s) 0.59: p = 0.044), matrix metalloproteinase-1 (MMP-1) (r(s) 0.83; p = 0.001), tissue inhibitor of metalloproteinase-2 (TIMP-2) (r(s) 0.74; p = 0.001) and TIMP-3 (r(s) 0.80; p = 0.001) mRNA expression. Moreover, AT2R mRNA and protein expression was significantly greater in the patients with biopsy-proven chronic allograft nephropathy (n = 9; p = 0.045 vs. no chronic allograft nephropathy and donor biopsy samples for mRNA analyses). CONCLUSIONS: These data demonstrate that AT2R mRNA is expressed in adult human renal tissue in the setting of renal transplantation. Its apparent association with matrix-modulating genes raises the hypothesis that AT2R mRNA expression may be linked with extracellular matrix regulation in the setting of chronic allograft nephropathy.