Endotheli n Stimulates M itogen - Activated Protein Kinase Activity in Mesangial Cells Through ETA 1

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 exammed. ET-1 activated both p42 and p44 MAP kinases with similar dose responses and different kinetics. The threshold for kinase activation was 10 M ET-1 . ET-1 stimulated p42 and p44 MAP kinases with similar rapid (5 mm) but different sustained activation of p42 (3 to#{243} h) and p44 (1 to 2 h). Endothelin-3 (ET-3) also activated both isoforms of MAP kinase but with a threshold at i0 M. Compared with El-i, ET-3 stimulated only a rapid increase of p42 MAP kinase activity. We further investigated which El receptors are coupled to MAP kinase activation. BQ-123, an ETA blocker, cornpletely blocked the responsiveness ofthe MAP kinase to either ET-i or ET-3. In Chinese hamster lung fibroblasts transfected with ETA or ETBcDNA, both receptors showed a rapid stimulation of MAP kinase in response to ET-i . These results suggest that El can activate MAP kinases through both ET receptors but act exclusively through ETA in glornerular mesangial cells. Received February 4, 1994. Accepted May 2, 1994. 2 correspondence to Dr. M.J. Dunn, Department of Medicine, Division of NephroI ogy, University Hospitals, cleveland, OH 44106. 1046-6673/0504-1 074$03.00/0 Journal of the American Society of Nephrology copyright © 1994 by the American Society of Nephrology