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We showed that two isoforms of platelet-derived growth factor (PDGF), AB and BB, stimulate the secretion of endothelin (ET)-1 from cultured rat mesangial cells. Then, we examined whether PDGF AB and BB stimulate mesangial cell proliferation through the modulation of the endogenous production of ET-1 in these cells. Mitogenesis experiments were assessed by tritiated thymidine incorporation into DNA under highest concentrations (10 ng/ml) of PDGF AB and BB in the presence and absence of anti-ET-1 antiserum or a selective A-type endothelin receptor (ETA receptor) antagonist, BQ-123. PDGF AB and BB potently stimulate thymidine incorporation. This stimulation was significantly attenuated in the presence of either anti-ET-1 antiserum or BQ-123 (10(-7)-10(-5)M). Results suggest that PDGF AB and BB stimulate ET-1 secretion in rat mesangial cells through PDGF beta-receptors, and endogenously produced ET-1 serves to modulate the mitogenic effect of PDGF AB and BB, probably via ETA receptors in these cells.

The present study examined the effects of atrial, brain, and C-type natriuretic peptides (ANP, BNP, and CNP, respectively) on endothelin-1 (ET-1) secretion after stimulation with arginine vasopressin (AVP), using cultured rat glomerular mesangial cells. AVP stimulated immunoreactive (ir) ET-1 secretion in a concentration-dependent manner via a receptor-mediated process. Rat ANP-(1-28) and rat BNP-45 potently inhibited this stimulated secretion in a concentration-dependent manner. Inhibition by ANP and BNP of AVP-stimulated ET-1 secretion was paralleled by an increase in the medium level of guanosine 3',5'-cyclic monophosphate (cGMP). The addition of a cGMP analogue, 8-bromo-cGMP, reduced the stimulated ET-1 secretion. CNP was much less effective than rat ANP-(1-28) or rat BNP-45 with respect to inhibiting irET-1 secretion and increasing cGMP levels. High-performance liquid chromatography indicated that the major component of irET-1 in the culture medium corresponds to ET-1-(1-21). These findings indicate that AVP stimulates ET-1 secretion in cultured rat mesangial cells and that rat ANP and BNP inhibit this stimulated secretion, probably through a cGMP-dependent process.