Vascular endothelin-1 (ET-1) levels are elevated in patients with renal allograft rejection, and the mitogenic and pressor actions of ET-1 might contribute to transplant vasculopathy, posttransplantation hypertension, and ischemia-reperfusion injury. In contrast, relatively little is known about tubular 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 analysis of tubular ET-1 was performed in renal biopsy specimens from 18 patients with acute rejection, 7 patients with chronic rejection, and 5 normal kidneys excised for localized neoplasm. The diagnosis of acute or chronic rejection in each patient was verified and graded using the Banff schema. Renal tubular epithelium from patients with allograft rejection had markedly elevated staining for ET-1 compared with normal kidneys. Tubular ET-1 levels were 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 follows: 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 prominent in both proximal and distal tubules, and we observed abundant ET-1 secretion from proximal tubular epithelium in culture. Moreover, ET-1 activated the c-fos immediate early gene promoter in proximal tubular cells transfected 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.