title: Endothelin-1 stimulates contraction of rat glomerular mesangial cells and potentiates beta-adrenergic-mediated cyclic adenosine monophosphate accumulation.
abstract: The newly isolated peptide, endothelin-1 (ET-1), is a potent pressor agent that reduces GFR and the glomerular ultrafiltration coefficient. Recent evidence demonstrates that ET-1 mobilizes intracellular Ca2+ [( Ca2+]i) in glomerular mesangial cells by activating the phosphoinositide cascade. The present experiments were designed to examine whether ET-1 stimulates mesangial cell contraction and regulates the synthesis of PGE2 and cAMP, which dampen vasoconstrictor-induced mesangial contraction. ET-1 (greater than or equal to 1 nM) reduced the cross-sectional area of rat mesangial cells cultured on three-dimensional gels of collagen type I. ET-1 also caused complex rearrangements of F-actin microfilaments consistent with a motile response. Contraction in response to ET-1 occurred only at concentrations that activate phospholipase C, and contraction was unaffected by blockade of dihydropyridine-sensitive Ca2+ channels. Elevation of [Ca2+]i with ionomycin, to equivalent concentrations of [Ca2+]i achieved with ET-1, also reduced mesangial cell cross-sectional area. ET-1 (0.1 microM) also evoked [3H]arachidonate release and a fivefold increase in PGE2 synthesis as well as increased synthesis of PGF2 alpha and small changes of TXB2. ET-1 caused a minor increase in intracellular cAMP accumulation only in the presence of 3-isobutyl-1-methylxanthine. ET-1 also amplified cAMP production in response to isoproterenol. TPA and ionomycin, alone and in combination, failed to mimic the potentiating effect of ET-1; however, indomethacin blocked ET-1-induced potentiation of isoproterenol-stimulated cAMP, which was restored by addition of exogenous 10 nM PGE2. Thus the present data demonstrate that ET-1 stimulates mesangial cell contraction via pharmacomechanical coupling and activates phospholipase A2 to produce PGE2, PGF2 alpha, and TXB2. ET-1 also amplified beta adrenergic-stimulated cAMP accumulation by a PGE2-dependent mechanism.
authors.affiliation: Department of Medicine, School of Medicine, Case Western Reserve University, Cleveland, Ohio.
authors.forename: M S
authors.initials: MS
authors.lastname: Simonson
authors.forename: M J
authors.initials: MJ
authors.lastname: Dunn
mesh_terms: D000818:Animals; D016718:Arachidonic Acid; D001095:Arachidonic Acids / Q000378:metabolism; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D000242:Cyclic AMP / Q000378:metabolism*; D015232:Dinoprostone / Q000378:metabolism / Q000494:pharmacology; D016232:Endothelins; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000502:physiology; D015759:Ionomycin / Q000494:pharmacology; D010455:Peptides / Q000494:pharmacology*; D051381:Rats; D011943:Receptors, Adrenergic, beta / Q000502:physiology*; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
chemical_list: D001095:Arachidonic Acids; D016232:Endothelins; D010455:Peptides; D011943:Receptors, Adrenergic, beta; D016718:Arachidonic Acid; D015759:Ionomycin; D000242:Cyclic AMP; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate; D002118:Calcium