Renin-angiotensin system gene expression in posttransplant hypertension predicts allograft function

Background. Registry analyses and single center studies have demonstrated t hat hypertension significantly increases the risk for chronic graft loss. T he graft itself may contribute to posttransplant hypertension, and intragra ft vasoactive hormones therefore, may be dysregulated in posttransplant hyp ertension. Methods. We used the reverse-transcription polymerase chain reaction to ass ess the intragraft regulation of renin-angiotensin system transcripts in bi opsy samples from 42 stable renal transplant patients with posttransplant h ypertension. We also examined mRNA expression of inducible nitric oxide syn thase, transforming growth factor-beta (TGF-beta), select cytokines, and me talloproteinase transcripts in biopsy tissue. Polymerase chain reaction pro ducts were quantitated using high performance liquid chromatography and nor malized to beta-actin mRNA expression. Serum creatinine, glomerular filtrat ion rate or creatinine clearance and tubular atrophy on biopsy were concurr ently assessed. Results. Renin and select Th1 cytokine mRNA expression correlated with bloo d pressure. Type 1 angiotensin II receptor mRNA expression significantly co rrelated with glomerular filtration rate or creatinine clearance (P=0.034) and inversely correlated with Th1 cytokines, inducible nitric oxide synthas e, and cyclooxygenase-1 mRNA expression (P less than or equal to 0.013 for each). Type 1 angiotensin II receptor mRNA also approached a significant in verse correlation with TGF-beta mRNA expression (P=0.09). Conversely, angio tensin-converting enzyme mRNA expression directly correlated with Th1 cytok ine (P less than or equal to 0.008 for each) and TGF-beta mRNA expression ( P=0.006). Type 1 angiotensin II receptor mRNA expression also correlated wi th matrix metalloproteinase-1 promoter region, tissue inhibitor of matrix m etalloproteinase-2 (TIMP-2) and tissue inhibitor of matrix metalloproteinas e-3 mRNA expression. Notably, matrix metalloproteinase-1 promoter region, t issue inhibitor of matrix metalloproteinase a, and tissue inhibitor of matr ix metalloproteinase-3 inversely correlated with TGF-beta mRNA expression ( P less than or equal to 0.0027 for each). Type 1 angiotensin II receptor mR NA expression at biopsy directly correlated with glomerular filtration rate at 2 year's follow-up. However, angiotensin-converting enzyme mRNA express ion at biopsy inversely correlated with glomerular filtration rate at 2 yea r's follow-up. Conclusions. These data suggest that allograft-level RAS gene expression ma y be predictive of future graft function in the setting of diastolic hypert ension.