ELEVATED NEOINTIMAL ENDOTHELIN-1 IN TRANSPLANTATION-ASSOCIATED ARTERIOSCLEROSIS OF RENAL-ALLOGRAFT RECIPIENTS

Background. Chronic renal allograft rejection is characterized histolo gically by transplantation-associated arteriosclerosis and glomerulosc lerosis (Tx-AA and Tx-AGS). Recent studies in animal models implicate the mitogenic and presser actions of endothelin-1 (ET-1) in Tx-AA. In humans, however, a link between elevated ET-1 secretion and Tx-AA or T x-AGS remains unclear. In this study we analyzed expression of ET-1 in the vasculature of renal transplant patients with chronic or acute re jection and in normal controls. Methods. Renal vascular and glomerular ET-1 was assessed by immunohistochemistry in 12 patients with clinica lly and histologically defined chronic rejection, in 11 patients with acute rejection, and in 5 normal kidneys. ET-1 staining was also corre lated with various clinical parameters and with a morphometric index o f neointima formation. ET-1 secretion was measured by ELISA in culture d human vascular cell types treated with T cell- and macrophage-associ ated cytokines. Results. We found that renal allografts with chronic r ejection and Tx-AA expressed 6.1-fold more ET-1 in the vasculature rel ative to allografts with acute rejection or to normal kidneys (P < 0.0 1). In Tx-AA, ET-1 was detected predominantly in the neointima, which contained mostly endothelial cells and smooth muscle cells. A strong p ositive correlation (r = 0.82, P < 0.01) was observed between vascular ET-1 peptide expression and hypertension in patients with chronic rej ection. We also showed that macrophage-associated cytokines, but not T cell-associated cytokines, stimulated ET-1 secretion in human endothe lial cells. vascular smooth muscle and mesangial cells. Conclusions. T hese results demonstrate that elevated ET-1 in the neointima is associ ated with Tx-AA and chronic rejection. In addition, these results poin t to an important role for endothelial dysfunction in chronic renal al lograft rejection.