Long-term activation of protein kinase C causes chronic Na/H antiporter stimulation in cultured proximal tubule cells

Shigeo Horie, Orson Moe, R. Tyler Miller, Robert J. Alpern

Research output: Contribution to journalArticlepeer-review

44 Scopus citations

Abstract

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 4α-PMA, an inactive analogue. The chronic effect of PMA was inhibited by 10 nM actinomycin D or 7 μM 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.

Original languageEnglish (US)
Pages (from-to)365-372
Number of pages8
JournalJournal of Clinical Investigation
Volume89
Issue number2
DOIs
StatePublished - 1992

Keywords

  • Actinomycin D
  • Cycloheximide
  • Memory
  • Northern blot
  • Phorbol esters

ASJC Scopus subject areas

  • Medicine(all)

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