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Type 2 angiotensin II receptor expression in human renal allografts: an association with chronic allograft
B N Becker1, L M Jacobson, D A Hullett
1Department of Medicine, University of Wisconsin, Department of Veterans Affairs Hospital, Madison 53705, USA. bnb@medicine.wisc.edu
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.
Insights
The type 2 angiotensin II receptor (AT2R) is expressed in adult human renal transplants. Its expression correlates with genes involved in extracellular matrix regulation and chronic allograft nephropathy.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- The renin-angiotensin system (RAS) is implicated in renal fibrosis via the type I angiotensin II receptor (AT1R).
- The role of the type 2 angiotensin II receptor (AT2R) in renal fibrosis in adult human tissue remains unclear.
Purpose of the Study:
- To investigate the expression and role of AT2R in adult human renal allografts.
- To determine if AT2R expression correlates with fibrotic processes and chronic rejection.
Main Methods:
- Reverse-transcription polymerase chain reaction (RT-PCR) was used to measure AT2R mRNA in renal transplant biopsy samples.
- Correlations between AT2R mRNA, matrix-modulating genes, and chronic rejection histology were assessed.
Main Results:
- AT2R mRNA was detected and confirmed by sequence analysis.
- AT2R mRNA expression positively correlated with angiotensinogen and matrix-modulating genes (TGF-beta, MMP-1, TIMP-2, TIMP-3).
- AT2R mRNA and protein levels were higher in patients with chronic allograft nephropathy.
Conclusions:
- AT2R mRNA is expressed in adult human renal transplants.
- AT2R expression is associated with matrix-modulating genes, suggesting a role in extracellular matrix regulation.
- These findings hypothesize a link between AT2R and the pathogenesis of chronic allograft nephropathy.