Endothelin stimulates mitogen-activated protein kinase activity in mesangial cells through ETA.
Accumulating evidence suggests that endothelin (ET) contributes to the pathophysiology of such disorders as acute renal failure, cyclosporine-mediated renal and vascular toxicity, and perhaps even glomerular inflammation. The postreceptor signaling pathways that mediate the actions of ET in these pathophysiologic conditions may include activation of kinase cascades. Thus, the effects of ET isopeptides on p42 and p44 mitogen-activated protein (MAP) kinase activity in rat glomerular mesangial cells were examined. ET-1 activated both p42 and p44 MAP kinases with similar dose responses and different kinetics. The threshold for kinase activation was 10(-9) M ET-1. ET-1 stimulated p42 and p44 MAP kinases with similar rapid (5 min) but different sustained activation of p42 (3 to 6 h) and p44 (1 to 2 h). Endothelin-3 (ET-3) also activated both isoforms of MAP kinase but with a threshold at 10(-7) M. Compared with ET-1, ET-3 stimulated only a rapid increase of p42 MAP kinase activity. We further investigated which ET receptors are coupled to MAP kinase activation. BQ-123, an ETA blocker, completely blocked the responsiveness of the MAP kinase to either ET-1 or ET-3. In Chinese hamster lung fibroblasts transfected with ETA or ETB cDNA, both receptors showed a rapid stimulation of MAP kinase in response to ET-1. These results suggest that ET can activate MAP kinases through both ET receptors but act exclusively through ETA in glomerular mesangial cells.
Department of Medicine, Case Western Reserve University, University Hospitals, Cleveland, OH.
Y
Y
Wang
J
J
Pouysségur
M J
MJ
Dunn
D000818:Animals; D017871:Calcium-Calmodulin-Dependent Protein Kinases / Q000378:metabolism*; D002460:Cell Line; D002478:Cells, Cultured; D006224:Cricetinae; D016232:Endothelins / Q000494:pharmacology*; D004789:Enzyme Activation / Q000187:drug effects; D005920:Glomerular Mesangium / Q000187:drug effects* / Q000201:enzymology*; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; D010456:Peptides, Cyclic / Q000494:pharmacology; D011505:Protein-Tyrosine Kinases / Q000378:metabolism*; D051381:Rats; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin / Q000187:drug effects / Q000235:genetics / Q000378:metabolism; D014162:Transfection
D016232:Endothelins; D010456:Peptides, Cyclic; D044022:Receptor, Endothelin A; D044023:Receptor, Endothelin B; D017466:Receptors, Endothelin; D011505:Protein-Tyrosine Kinases; D017871:Calcium-Calmodulin-Dependent Protein Kinases; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D020928:Mitogen-Activated Protein Kinases; C072247:cyclo(Trp-Asp-Pro-Val-Leu)