title: An orally active ETA/ETB 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 ETA receptor (10 and 6 times compared to controls, respectively), but not of the ETB 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 come tubular cells was observed. The administration of bosentan, an ETA/ETB receptor antagonist, had a beneficial effect on the evolution of nephritis preventing the appearance of intense proteinuria (76 +/- 35 vs. 380 +/- 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 microliters/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-1 participates in the pathogenesis of proteinuria and glomerular injury in a model of proliferative nephritis. The nonpeptidic orally active ETA/ETB receptor antagonists could be useful in the treatment of some human nephritis.
authors.affiliation: Renal Research Laboratory, Fundación liménez Díaz, Universidad Autónoma, Madrid, Spain.
authors.forename: D
authors.initials: D
authors.lastname: Gómez-Garre
authors.forename: R
authors.initials: R
authors.lastname: Largo
authors.forename: X H
authors.initials: XH
authors.lastname: Liu
authors.forename: S
authors.initials: S
authors.lastname: Gutierrez
authors.forename: M J
authors.initials: MJ
authors.lastname: López-Armada
authors.forename: I
authors.initials: I
authors.lastname: Palacios
authors.forename: J
authors.initials: J
authors.lastname: Egido
mesh_terms: D000818:Animals; D000918:Antibody Specificity; D001794:Blood Pressure; D000077300:Bosentan; D004195:Disease Models, Animal; D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1 / Q000097:blood / Q000276:immunology / Q000652:urine; D016232:Endothelins / Q000235:genetics; D005260:Female; D015432:Glomerulonephritis, Membranoproliferative / Q000150:complications / Q000188:drug therapy*; D007150:Immunohistochemistry; D017403:In Situ Hybridization; D007668:Kidney / Q000737:chemistry / Q000503:physiopathology; D007677:Kidney Function Tests; D011498:Protein Precursors / Q000235:genetics; D011507:Proteinuria / Q000188:drug therapy* / Q000209:etiology; D012333:RNA, Messenger / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin / Q000235:genetics; D013449:Sulfonamides / Q000494:pharmacology
chemical_list: D065128:Endothelin Receptor Antagonists; D019332:Endothelin-1; D016232:Endothelins; D011498:Protein Precursors; D012333:RNA, Messenger; D044022:Receptor, Endothelin A; D017466:Receptors, Endothelin; D013449:Sulfonamides; D000077300:Bosentan