ENDOTHELIN-1 AND ENDOTHELIN-B TYPE RECEPTOR ARE INDUCED IN MESANGIAL PROLIFERATIVE NEPHRITIS IN THE RAT

We studied whether endothelin-1 (ET-1) and its receptor subtypes (ETAR , endothelin A type receptor; and ETBR, B type receptor) were up-regul ated in the glomerulus of a rat model of mesangial proliferative glome rulonephritis induced by anti-thymocyte serum (anti-Thy-1 GN). A marke d 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, r espectively), corresponding to the time of mesangial cell proliferatio n, to the time of macrophage infiltration into glomeruli, and also to the time of increase in glomerular PDGF B-chain mRNA expression. The l ocalization of ET-1 protein in the mesangial area and along the inner aspect of the glomerular capillary wall was also demonstrated by immun ohistochemistry from day 3 and maximal at day 6. The major source of t he cells expressing ET-1 in glomeruli appeared to be mesangial cells, glomerular endothelial cells and monocyte/macrophages. Furthermore, bo th 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 im munoreactivity. Glomerular expression of ETBR mRNA increased in anti-T hy-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 ETA R mRNA expression. These results suggest that pre-proET-1 mRNA, which is induced in anti-Thy-1 GN, is linked primarily with ETBR mRNA expres sion. Up-regulated expressions of both pre-proET-1 mRNA and ET-1 prote in, and increased urinary ET-1 excretion in the proliferative phase of anti-Thy-1 GN were dramatically suppressed by complement depletion wi th cobra venom factor treatment, and these ruled out the possibility t hat the change of ET-1 might be from the direct effect by anti-Thy-1 a ntibody itself. In conclusion, there is an induction of glomerular ET- 1 and ETBR gene transcription and ET-1 protein synthesis in rat mesang ial proliferative glomerulonephritis. PreproET-1 mRNA expression was c losely associated with PDGF B-chain mRNA expression and the up-regulat ion of ET-1 expression may stimulate PDGF-dependent mesangial cell pro liferation in anti-Thy-1 nephritis. ET-1 production in glomeruli may a llow an amplification of mesangial cell proliferation and subsequent m atrix expansion in this model.