Endothelin-1 in the kidney and urine of patients with glomerular disease and proteinuria.

Abstract

Endothelin-1 (ET-1) is a strong vasoconstrictive peptide that is involved in the pathogenesis of arterial hypertension. There is increasing evidence, based on studies in experimental animals, that endothelin-1 is produced by tubular epithelial cells in response to activation by filtered protein and is involved in the development of renal scarring. The aim of this study is to examine the distribution of ET-1 in the renal tissue of patients with heavy proteinuria and to estimate the changes in its urinary excretion after immunosuppressive therapy. Twenty-four patients with severe proteinuria (7.5 +/- 6.5 g/24 h) due to different types of glomerular disease and normal renal function (creatinine clearance 91 +/- 14 ml/ min) were investigated. All patients underwent a renal biopsy and commenced on immunosuppressive therapy with corticosteroids and cyclosporin A. The localization of ET-1 in the renal tissue was examined by immunohistochemistry and compared to control renal tissue from 9 patients who underwent nephrectomies because of hypernephroma. In patients with proteinuria, endothelin-1 excretion in the urine at diagnosis was determined by radioimmunoassay and compared to that of 14 healthy subjects. A second measurement of urinary ET-1 excretion was performed after remission of proteinuria or 6 months after the initiation of treatment in patients with persistent nephrotic syndrome. ET-1 in renal tissue of patients and controls was localized within the cytoplasm of endothelial cells. In nephrotic patients, it was also localized within the cytoplasm of tubular epithelial cells. Urinary ET-1 levels were higher in nephrotic patients compared to healthy subjects (746 +/- 180 ng/24 h vs 410 +/- 112 ng/ml, p < 0.001). In 17 of 24 patients who showed remission of proteinuria with immunosuppressive therapy, the urinary ET-1 levels decreased (from 803 +/- 168 ng/24 h to 511 +/- 80 ng/24 h, p < 0.001) whereas in 7 patients with persistent proteinuria, urinary ET-1 excretion remained elevated. The increased urinary excretion of ET-1 in patients with severe proteinuria followed by a significant decrease after remission ofproteinuria with immunosuppressive treatment, along with its expression within tubular epithelial cells, suggests a possible relationship between proteinuria and renal ET-1 production.