Regulation of endothelin-1 production in cultured rat mesangial cells.
We investigated the regulatory mechanisms of endothelin (ET)-1 production in cultured rat mesangial cells (MC), with a special focus on the roles of protein kinase A (PKA)- and protein kinase C (PKC)-mediated signaling systems. Vasoactive agents and growth promoting factors, including platelet-derived growth factor, vasopressin and thrombin, which act through receptors coupled to the phospholipase C-mediated signaling system, as well as phorbol ester and fetal calf serum stimulated ET-1 production. This effect was attenuated in PKC-depleted or H-7 (a PKC inhibitor) treated MC. On the other hand, an increase in intracellular cyclic AMP by forskolin or beta-adrenergic agonist, isoproterenol, which act as anti-mitogenic agents, inhibited serum-stimulated ET-1 production. In addition this effect was mimicked by the addition of 8-bromo-cyclic AMP to the medium. The effect of isoproterenol was abolished by propranolol. H-8, a PKA inhibitor, attenuated the inhibitory effect of forskolin. These findings suggest that ET-1 production in MC is regulated by interaction of both positive and negative signals mediated by PKC- and PKA-dependent mechanisms.
Sakamoto
H
H
Second Department of Internal Medicine, Tokyo Medical and Dental University, Japan.
Sasaki
S
S
Nakamura
Y
Y
Fushimi
K
K
Marumo
F
F
D000818:Animals; D002417:Cattle / Q000097:blood / Q000196:embryology; D002478:Cells, Cultured; D005576:Colforsin / Q000494:pharmacology; D000242:Cyclic AMP / Q000494:pharmacology; D016232:Endothelins / Q000037:antagonists & inhibitors / Q000096:biosynthesis*; D004789:Enzyme Activation; D005920:Glomerular Mesangium / Q000166:cytology / Q000378:metabolism*; D007546:Isoquinolines / Q000494:pharmacology; D008938:Mitosis / Q000187:drug effects; D011493:Protein Kinase C / Q000378:metabolism; D047428:Protein Kinase Inhibitors; D011494:Protein Kinases / Q000502:physiology; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D016232:Endothelins; D007546:Isoquinolines; D047428:Protein Kinase Inhibitors; D005576:Colforsin; C053177:N-(2-(methylamino)ethyl)-5-isoquinolinesulfonamide; D000242:Cyclic AMP; D011494:Protein Kinases; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate