An orally active ET(A)/ET(B) receptor antagonist ameliorates proteinuria and glomerular lesions in rats with proliferative nephritis

Abstract

The proliferation of mesangial cells and the extracellular matrix expansion constitute the most outstanding morphological aspects of the majority of progressive glomerular diseases. In vitro, endothelin-1 (ET-1) is mitogenic for mesangial cells and induces matrix protein synthesis. We studied the possible participation of ET-1 in the pathogenesis of renal damage in a normotensive model of proliferative nephritis. Coincidentally with maximal proteinuria and glomerular lesions, an increase was found in the glomerular mRNA expression of preproET-1 and the ET(A) receptor (10 and 6 times compared to controls, respectively), but not of the ET(B) receptor, and in ET-1 urinary excretion (217 ± 33 vs. 84 ± 4 pg ET-1/24 hr, N = 4 to 5, P < 0.05). By in situ hybridization, an increase in preproET-1 mRNA expression in glomerular endothelial, epithelial and mesangial cells, and in some tubular cells was observed. The administration of bosentan, an ET(A)/ET(B) receptor antagonist, had a beneficial effect on the evolution of nephritis, preventing the appearance of intense proteinuria (76 ± 35 vs. 350 ± 77 mg/24 hr, N = 4 to 5, P < 0.05), the morphological lesions and the renal function impairment (creatinine clearance 367 ± 46 vs. 268 ± 33 μl/min/100 g, N = 4 to 5). Simultaneously, there was a decrease in ET-1 urinary excretion (88 ± 14 vs. 217 ± 33 pgET-1/24 hr, N = 4 to 5, P < 0.05) and in the renal preproET-1 mRNA expression. The mean systolic blood pressures remained in the normal range in all animals. These data indicate that ET-1 participates in the pathogenesis of proteinuria and glomerular injury in a model of proliferative nephritis. The nonpeptidic orally active ET(A)/ET(B) receptor antagonists could be useful in the treatment of some human nephritis.