Elevated neointimal endothelin-1 in transplantation-associated arteriosclerosis of renal allograft recipients.
BACKGROUND
Chronic renal allograft rejection is characterized histologically by transplantation-associated arteriosclerosis and glomerulosclerosis (Tx-AA and Tx-AGS). Recent studies in animal models implicate the mitogenic and pressor actions of endothelin-1 (ET-1) in Tx-AA. In humans, however, a link between elevated ET-1 secretion and Tx-AA or Tx-AGS remains unclear. In this study we analyzed expression of ET-1 in the vasculature of renal transplant patients with chronic or acute rejection and in normal controls.


METHODS
Renal vascular and glomerular ET-1 was assessed by immunohistochemistry in 12 patients with clinically and histologically defined chronic rejection, in 11 patients with acute rejection, and in 5 normal kidneys. ET-1 staining was also correlated with various clinical parameters and with a morphometric index of neointima formation. ET-1 secretion was measured by ELISA in cultured human vascular cell types treated with T cell- and macrophage-associated cytokines.


RESULTS
We found that renal allografts with chronic rejection and Tx-AA expressed 6.1-fold more ET-1 in the vasculature relative to allografts with acute rejection or to normal kidneys (P < 0.01). In Tx-AA, ET-1 was detected predominantly in the neointima, which contained mostly endothelial cells and smooth muscle cells. A strong positive correlation (r = 0.82, P < 0.01) was observed between vascular ET-1 peptide expression and hypertension in patients with chronic rejection. We also showed that macrophage-associated cytokines, but not T cell-associated cytokines, stimulated ET-1 secretion in human endothelial cells, vascular smooth muscle and mesangial cells.


CONCLUSIONS
These results demonstrate that elevated ET-1 in the neointima is associated with Tx-AA and chronic rejection. In addition, these results point to an important role for endothelial dysfunction in chronic renal allograft rejection.
Simonson
M S
MS
Department of Medicine, School of Medicine, Case Western Reserve University, and University Hospitals of Cleveland, Ohio 44106, USA. mss5@po.cwru.edu
Emancipator
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SN
Knauss
T
T
Hricik
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DE
D000293:Adolescent; D000328:Adult; D000368:Aged; D001161:Arteriosclerosis / Q000097:blood* / Q000209:etiology; D002478:Cells, Cultured; D016207:Cytokines / Q000494:pharmacology; D019332:Endothelin-1 / Q000097:blood* / Q000378:metabolism; D005260:Female; D005920:Glomerular Mesangium / Q000473:pathology; D006084:Graft Rejection; D006801:Humans; D016030:Kidney Transplantation / Q000276:immunology*; D008297:Male; D008875:Middle Aged; D009131:Muscle, Smooth, Vascular / Q000737:chemistry*; D014184:Transplantation, Homologous
D016207:Cytokines; D019332:Endothelin-1