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

The proliferation of mesangial cells and the: extracellular matrix expansion constitute the most outstanding morphological aspects of thr majority of progressive glomerular diseases. In vitro, endothelin-l (ET-I) is mitogenic for mesangial cells and induces matrix protein synthesis. We studied the possible participation of ET-I in the pathogenesis of renal damage in a normotensive model oi 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, A:= 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 tilt: evolution of nephritis. preventing the appearance of intense proteinuria (76 +/- 35 vs. 380 +/- 77 mg/24 kr, N = 4 to 5, P < 0.05), the morphological lesions and thr renal function impairment (creatinine clearance 367 +/- 46 vs. 268 +/- 33 mu l/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 = 4:5, 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-I participates in the pathogenesis of proteinuria and glomerular injury in a modal of proliferative nephritis. The nonpeptidic orally active ET(A)/ET(B) receptor antagonists could be useful in the treatment of some human nephritis.