EFFECTS AND INTERACTIONS OF ENDOTHELIN-1 AND ANGIOTENSIN-II ON MATRIXPROTEIN EXPRESSION AND SYNTHESIS AND MESANGIAL CELL-GROWTH

Mesangial cell growth and accumulation of extracellular matrix protein s constitute key features of progressive glomerular injury. Endothelin -1 (ET-1) and angiotensin II (Ang II), two potent vasoconstrictor agen ts, evoke a number of similar responses in mesangial cells. In rat mes angial cells, we compared ET-1 and Ang II effects on matrix protein pr oduction and cell proliferation as well as the potential interaction b etween the two hormones. When cells in 0.5% fetal calf serum were incu bated 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 demonst rated that endothelin subtype A (ET(A)) and angiotensin type 1 (AT(1)) receptors were involved. Preincubation of cells with two different pr otein kinase C inhibitors or with a neutralizing anti-transforming gro wth factor-p antibody, but not an unrelated IgG, diminished the peptid e-induced fibronectin synthesis. A dual interrelation seems to exist b etween ET-1 and Ang II. Thus, the AT(1) receptor antagonist losartan a nd the angiotensin-converting enzyme inhibitors quinaprilat and captop ril diminished the ET-1-mediated effects, whereas the ET(A) receptor a ntagonist BQ-123 diminished the Ang II-induced fibronectin synthesis a nd mesangial cell proliferation. Our results suggest that ET-1 and Ang II stimulate matrix protein synthesis and mesangial cell mitogenesis through ET(A) and AT(1) receptors, respectively, by complicated mechan isms, implicating protein kinase C activation, synthesis of transformi ng growth factor-beta, and release of one peptide by the other. These data could be important for a better understanding of the participatio n of vasoactive substances in the pathogenesis of glomerulosclerosis.