Elevated endothelin-1 in tubular epithelium is associated with renal allograft rejection

Vascular endothelin-1 (ET-1) levels are elevated in patients with renal all ograft rejection, and the mitogenic and presser actions of ET-1 might contr ibute to transplant vasculopathy, posttransplantation hypertension, and isc hemia-reperfusion injury. In contrast, relatively little is known about tub ular expression of ET-1 in acute or chronic rejection of renal allografts, We sought to determine whether tubular ET-1 levels were altered in patients with acute or chronic renal allograft rejection. Immunohistochemical analy sis of tubular ET-1 was performed in renal biopsy specimens from 18 patient s with acute rejection, 7 patients with chronic rejection, and 5 normal kid neys excised for localized neoplasm, The diagnosis of acute or chronic reje ction in each patient was verified and graded using the Banff schema, Renal tubular epithelium from patients with allograft rejection had markedly ele vated staining for ET-1 compared with normal kidneys. Tubular ET-1 levels w ere elevated in 18 of 18 patients with acute rejection and 5 of 7 patients with chronic rejection, Tubular ET-1 staining was graded from 0 to +3 as fo llows: normal kidneys, 1.2 +/- 0.2; acute rejection, 2.3 +/- 0.4 (P < 0.01) ; and chronic rejection, 2.2 +/- 0.5 (P < 0.01), ET-1 staining was prominen t in both proximal and distal tubules, and we observed abundant ET-1 secret ion from proximal tubular epithelium in culture. Moreover, ET-1 activated t he c-fos immediate early gene promoter in proximal tubular cells transfecte d with a c-fos luciferase reporter. We conclude that elevated tubular ET-1 levels are associated with acute and chronic rejection of renal allografts, Our results also suggest distinct pathophysiological roles for the tubular and vascular ET-1 systems in renal allograft rejection. (C) 2000 by fhe Na tional Kidney Foundation, Inc.