Effects and Interactions of Endothelin-1 and Angiotensin II on Matrix Protein Expression and Synthesis and Mesangial Cell Growth

• Published in: Hypertension (Dallas, Tex. 1979) Tex. 1979), 1996-04, Vol.27 (4), p.885-892
• Main Authors: Gomez-Garre, Dulcenombre, Ruiz-Ortega, Marta, Ortego, Monica, Largo, Raquel, Lopez-Armada, Maria Jose, Plaza, Juan J, Gonzalez, Eva, Egido, Jesus
• Format: Article
• Language: English
• Subjects: Angiotensin II - pharmacology; Animals; Biological and medical sciences; Cell Division - drug effects; Cells, Cultured; Drug Interactions; Endocrine kidney. Renin-angiotensin-aldosterone system; Endothelins - pharmacology; Extracellular Matrix Proteins - biosynthesis; Fundamental and applied biological sciences. Psychology; Glomerular Mesangium - cytology; Glomerular Mesangium - metabolism; Male; Rats; Rats, Sprague-Dawley; Vertebrates: endocrinology
• ISSN: 0194-911X; 1524-4563
• DOI: 10.1161/01.hyp.27.4.885

Mesangial cell growth and accumulation of extracellular matrix proteins constitute key features of progressive glomerular injury. Endothelin-1 (ET-1) and angiotensin II (Ang II), two potent vasoconstrictor agents, evoke a number of similar responses in mesangial cells. In rat mesangial cells, we compared ET-1 and Ang II effects on matrix protein production and cell proliferation as well as the potential interaction between the two hormones. When cells in 0.5% fetal calf serum were incubated for 24 hours with various concentrations of ET-1 or Ang II, both peptides stimulated, in a dose-dependent manner, fibronectin and type IV collagen mRNA expression, fibronectin synthesis, and mitogenesis. Incubation with specific receptor antagonists of both hormones demonstrated that endothelin subtype A (ETA) and angiotensin type 1 (AT1) receptors were involved. Preincubation of cells with two different protein kinase C inhibitors or with a neutralizing anti-transforming growth factor-beta antibody, but not an unrelated IgG, diminished the peptide-induced fibronectin synthesis. A dual interrelation seems to exist between ET-1 and Ang II. Thus, the AT (1) receptor antagonist losartan and the angiotensin-converting enzyme inhibitors quinaprilat and captopril diminished the ET-1-mediated effects, whereas the ETA receptor antagonist BQ-123 diminished the Ang II-induced fibronectin synthesis and mesangial cell proliferation. Our results suggest that ET-1 and Ang II stimulate matrix protein synthesis and mesangial cell mitogenesis through ETA and AT1 receptors, respectively, by complicated mechanisms, implicating protein kinase C activation, synthesis of transforming growth factor-beta, and release of one peptide by the other. These data could be important for a better understanding of the participation of vasoactive substances in the pathogenesis of glomerulosclerosis. (Hypertension. 1996;27:885-892.)