Long-term activation of protein kinase c causes chronic Na/H antiporter stimulation in cultured proximal tubule cells.
To examine the role of protein kinase C as a chronic regulator of proximal tubule Na/H antiporter activity, the effect of phorbol 12-myristate 13-acetate (PMA) on the Na/H antiporter was studied in cultured proximal tubule cells. Short-term activation of protein kinase C by 5 min exposure to PMA caused an acute increase in Na/H antiporter activity that was not prevented by cycloheximide or actinomycin D and did not persist 24 h later. Long-term activation of protein kinase C by 2 h exposure to PMA caused a dose-dependent increase in Na/H antiporter activity 24 h later. This latter effect was due to protein kinase C activation in that it was inhibited by sphingosine and was not seen with 4 alpha-PMA, an inactive analogue. The chronic effect of PMA was inhibited by 10 nM actinomycin D or 7 microM cycloheximide. Proximal tubule cells exposed to PMA for 2 h demonstrated a two- to threefold increase in Na/H antiporter mRNA (mRNANa/H) abundance 4 h later. In conclusion, short-term activation of protein kinase C leads to a transient increase in Na/H antiporter activity that is independent of transcription and translation, whereas long-term activation of protein kinase C causes a persistent increase in antiporter activity that is dependent on transcription and translation and is associated with increased mRNANa/H abundance. This latter effect may mediate increased Na/H antiporter activity in a number of chronic conditions.
Horie
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Department of Internal Medicine, University of Texas Southwestern Medical Center, Dallas 75235.
Moe
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Miller
R T
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Alpern
R J
RJ
D000818:Animals; D002352:Carrier Proteins / Q000032:analysis* / Q000235:genetics; D002478:Cells, Cultured; D004789:Enzyme Activation; D007687:Kidney Tubules, Proximal / Q000378:metabolism*; D008297:Male; D014176:Protein Biosynthesis; D011493:Protein Kinase C / Q000502:physiology*; D012333:RNA, Messenger / Q000032:analysis; D011817:Rabbits; D017923:Sodium-Hydrogen Exchangers; D013755:Tetradecanoylphorbol Acetate / Q000494:pharmacology; D014158:Transcription, Genetic
D002352:Carrier Proteins; D012333:RNA, Messenger; D017923:Sodium-Hydrogen Exchangers; D011493:Protein Kinase C; D013755:Tetradecanoylphorbol Acetate