Effects of specific endothelin-1 receptor antagonists on proliferation and fibronectin production of glomerular mesangial cells stimulated with Angiotensin II.

Angiotensin II (Ang-II) is a potent vasoactive hormone, which plays an important role in the pathogenesis of glomerulosclerosis. Ang-II activates many cytokine systems in the kidney. Recent studies indicate that Ang-II is closely related to the activation of the endothelin-1 (ET-1) system. The present study was designed to measure the [H3]-thymidine uptake and fibronectin production of cultured rat mesangial cells stimulated with Ang-II, and to evaluate the effects of specific ET-1 receptor antagonists, BQ123 (type A receptor antagonist) and IRL1038 (type B receptor antagonist) on the cells. ET-1 was measured by radioimmunoassay and fibronectin by Western blot analysis. The results were as follows: (1) Ang-II enhanced ET-1 production, [H3]-thymidine uptake, number of cells, and fibronectin production of mesangial cells; (2) all the baseline [H3]-thymidine uptake, number of cells, and fibronectin production of mesangial cells can be partly suppressed by BQ123, but not by IRL1038; (3) the increment of Ang-II-enhanced number of cells can be partly suppressed by BQ123, but not by IRL1038; and (4) the increment of Ang-II-enhanced fibronectin production can be partly suppressed by both BQ123 and IRL1038. Our results indicate that Ang-II is an active stimulant for the proliferation and fibronectin production of mesangial cells, and the effect is partly suppressed mainly by ET-1 type A receptor antagonists.