Type 2 angiotensin II receptor expression in human renal allografts: An association with chronic allograft nephropathy

Aims: The renin-angiotensin system (RAS) has been implicated in renal fibrosis through activation of the type 1 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-β (TGF-β) (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.