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Renin-angiotensin system gene expression in post-transplant hypertension predicts allograft function
B N Becker1, L M Jacobson, Y T Becker
1Department of Medicine and Department of Veterans Affairs Hospital, University of Wisconsin, Madison 53792, USA.
Insights
Investigating gene expression in kidney transplant patients with hypertension revealed that renin-angiotensin system (RAS) gene expression in the graft may predict future kidney function. This finding offers insights into managing post-transplant hypertension and chronic graft loss.
Area of Science:
- Nephrology
- Immunology
- Molecular Biology
Background:
- Hypertension is a significant risk factor for chronic graft loss after kidney transplantation.
- Post-transplant hypertension may be influenced by dysregulated vasoactive hormones within the graft.
Purpose of the Study:
- To investigate the intragraft regulation of renin-angiotensin system (RAS) transcripts in renal transplant recipients with post-transplant hypertension.
- To examine the correlation between RAS gene expression and graft function, blood pressure, and inflammatory markers.
Main Methods:
- Reverse-transcription polymerase chain reaction (RT-PCR) was used to analyze mRNA expression of RAS components, inducible nitric oxide synthase, TGF-beta, cytokines, and metalloproteinases in kidney biopsy samples from 42 patients.
- Gene expression levels were quantified using high-performance liquid chromatography and normalized to beta-actin.
- Serum creatinine, glomerular filtration rate (GFR), and histological findings (tubular atrophy) were concurrently assessed.
Main Results:
- Renin and Th1 cytokine mRNA expression correlated with blood pressure.
- Type 1 angiotensin II receptor mRNA expression correlated with GFR and inversely with Th1 cytokines and inducible nitric oxide synthase.
- Angiotensin-converting enzyme (ACE) mRNA expression correlated with Th1 cytokines and TGF-beta. ACE mRNA at biopsy inversely correlated with GFR at 2-year follow-up.
Conclusions:
- Intragraft RAS gene expression, particularly ACE, may serve as a predictive marker for future graft function in patients with post-transplant diastolic hypertension.
- These findings highlight the potential role of intragraft molecular mechanisms in the development of post-transplant hypertension and graft dysfunction.
Background:
Registry analyses and single-center studies have demonstrated that hypertension significantly increases the risk for chronic graft loss. The graft itself may contribute to posttransplant hypertension, and intragraft vasoactive hormones therefore, may be dysregulated in posttransplant hypertension.
Methods:
We used the reverse-transcription polymerase chain reaction to assess the intragraft regulation of renin-angiotensin system transcripts in biopsy samples from 42 stable renal transplant patients with posttransplant hypertension. We also examined mRNA expression of inducible nitric oxide synthase, transforming growth factor-beta (TGF-beta), select cytokines, and metalloproteinase transcripts in biopsy tissue. Polymerase chain reaction products were quantitated using high performance liquid chromatography and normalized to beta-actin mRNA expression. Serum creatinine, glomerular filtration rate or creatinine clearance and tubular atrophy on biopsy were concurrently assessed.
Results:
Renin and select Thl cytokine mRNA expression correlated with blood pressure. Type 1 angiotensin II receptor mRNA expression significantly correlated with glomerular filtration rate or creatinine clearance (P = 0.034) and inversely correlated with Th1 cytokines, inducible nitric oxide synthase, and cyclooxygenase-1 mRNA expression (P< or =0.013 for each). Type 1 angiotensin II receptor mRNA also approached a significant inverse correlation with TGF-beta mRNA expression (P = 0.09). Conversely, angiotensin-converting enzyme mRNA expression directly correlated with Thl cytokine (P< or =0.008 for each) and TGF-beta mRNA expression (P = 0.006). Type 1 angiotensin II receptor mRNA expression also correlated with matrix metalloproteinase-1 promoter region, tissue inhibitor of matrix metalloproteinase-2 (TIMP-2) and tissue inhibitor of matrix metalloproteinase-3 mRNA expression. Notably, matrix metalloproteinase-1 promoter region, tissue inhibitor of matrix metalloproteinase-2, and tissue inhibitor of matrix metalloproteinase-3 inversely correlated with TGF-beta mRNA expression (P< or =0.0027 for each). Type 1 angiotensin II receptor mRNA expression at biopsy directly correlated with glomerular filtration rate at 2 year's follow-up. However, angiotensin-converting enzyme mRNA expression at biopsy inversely correlated with glomerular filtration rate at 2 year's follow-up.
Conclusions:
These data suggest that allograft-level RAS gene expression may be predictive of future graft function in the setting of diastolic hypertension.