Cyclosporin A inhibits protein kinase C activity: a contributing mechanism in the development of nephrotoxicity?
Cyclosporin A modifies many intracellular functions in a variety of different cells. This study investigated the potential interaction between cyclosporin A and protein kinase C, as a possible mechanism for the development of nephrotoxicity. The activity of protein kinase C, in the cytosol of renal epithelial cells, was shown to be significantly inhibited in a dose-dependent manner by CSA. Activation of protein kinase C by 12-O-tetradecanoylphorbol-13-acetate (phorbol ester) in rat mesangial cells in culture leads to an increase in PGE2 release. Phorbol ester stimulated PGE2 release was significantly inhibited by cyclosporin A. These results would suggest that intracellular site of action of cyclosporin A, in producing alterations in intracellular function and toxicity, may be at the level of protein kinase C.
Walker
R J
RJ
Department of Renal Medicine, Royal Prince Alfred Hospital, Camperdown NSW, Australia.
Lazzaro
V A
VA
Duggin
G G
GG
Horvath
J S
JS
Tiller
D J
DJ
D000818:Animals; D002460:Cell Line; D003524:Cyclosporins / Q000494:pharmacology* / Q000633:toxicity; D003600:Cytosol / Q000201:enzymology; D015232:Dinoprostone / Q000378:metabolism; D004285:Dogs; D004789:Enzyme Activation / Q000187:drug effects; D004848:Epithelium / Q000201:enzymology; D005920:Glomerular Mesangium / Q000201:enzymology / Q000378:metabolism; D007668:Kidney / Q000201:enzymology; D007674:Kidney Diseases / Q000139:chemically induced*; D011493:Protein Kinase C / Q000037:antagonists & inhibitors*; D051381:Rats; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology
D003524:Cyclosporins; D011493:Protein Kinase C; D015232:Dinoprostone; D013755:Tetradecanoylphorbol Acetate