We studied whether endothelin-1 (ET-1) and its receptor subtypes (ETAR, endothelin A type receptor; and ETBR, B type receptor) were up-regulated in the glomerulus of a rat model of mesangial proliferative glomerulonephritis induced by anti-thymocyte serum (anti-Thy-1 GN). A marked increase in preproET-1 mRNA could be demonstrated in glomerular RNA 3 and six days after disease induction (4.1- and 4.9-fold vs. day 0, respectively), corresponding to the time of mesangial cell proliferation, to the time of macrophage infiltration into glomeruli, and also to the time of increase in glomerular PDGF B-chain mRNA expression. The localization of ET-1 protein in the mesangial area and along the inner aspect of the glomerular capillary wall was also demonstrated by immunohistochemistry from day 3 and maximal at day 6. The major source of the cells expressing ET-1 in glomeruli appeared to be mesangial cells, glomerular endothelial cells and monocyte/macrophages. Furthermore, both gene and protein expression of ET-1 were associated with increased urinary excretion of ET-1. There was no increase in the plasma ET-1 immunoreactivity. Glomerular expression of ETBR mRNA increased in anti-Thy-1 GN (1.5-fold vs. day 0 at day 3 after disease induction, 3.6-fold at day 6 and 2.7-fold at day 10), but there was minimal change in ETAR mRNA expression. These results suggest that preproET-1 mRNA, which is induced in anti-Thy-1 GN, is linked primarily with ETBR mRNA expression. Up-regulated expressions of both preproET-1 mRNA and ET-1 protein, and increased urinary ET-1 excretion in the proliferative phase of anti-Thy-1 GN were dramatically suppressed by complement depletion with cobra venom factor treatment, and these ruled out the possibility that the change of ET-1 might be from the direct effect by anti-Thy-1 antibody itself. In conclusion, there is an induction of glomerular ET-1 and ETBR gene transcription and ET-1 protein synthesis in rat mesangial proliferative glomerulonephritis. PreproET-1 mRNA expression was closely associated with PDGF B-chain mRNA expression and the up-regulation of ET-1 expression may stimulate PDGF-dependent mesangial cell proliferation in anti-Thy-1 nephritis. ET-1 production in glomeruli may allow an amplification of mesangial cell proliferation and subsequent matrix expansion in this model.
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