Role of c-SRC and ERK in acid-induced activation of NHE3

Hirohiko Tsuganezawa, Soichiro Sato, Yasuyoshi Yamaji, Patricia A. Preisig, Orson W. Moe, Robert J. Alpern

Research output: Contribution to journalArticlepeer-review

68 Scopus citations


Background. In the renal proximal tubule, chronic acidosis causes increases in apical membrane NHE3 activity, which serve to increase transepithelial H+ secretion and return systemic pH to normal levels. Incubation of cultured renal epithelial cells in acid media activates c-Src. Methods. OKP cells were incubated in control (pH 7.4) or acid (7.0) media, and NHE3 activity measured as cytoplasmic pH (pHi) recovery from an acid load using BCECF. c-Src, ERK, and JNK kinase activities were measured by immune complex kinase assays with enolase, MBP, and GST-c-Jun, respectively, as substrates in the in vitro assays. To determine the role of c-Src in acid-induced NHE3 activation, cells were transfected with vector alone or a dominant negative c-Src (c-SrcK295M). Results. Expression of dominant negative c-srcK295M in OKP cells prevented acid-induced activation of NHE3. Incubation of OKP cells in acid media increased ERK activity and c-fos expression, but did not increase JNK activity. Acidosis in vivo also activated renal cortical c-Src and ERK kinases, whereas incubation of 3T3 cells in acid media activated c-Src but not ERK kinase. Expression of c-srcK295M did not affect ERK or c-fos activation by acid incubation. Inhibition of MEK with PD98059 inhibited activation of NHE3 by acid incubation. Conclusions. These studies suggest that acidosis activates c-Src and MEK/ERK/c-fos. While both pathways are necessary for activation of NHE3, they are activated independently.

Original languageEnglish (US)
Pages (from-to)41-50
Number of pages10
JournalKidney international
Issue number1
StatePublished - 2002


  • JNK
  • MAP kinase
  • NIH 3T3 cells
  • Na/H antiporter
  • OKP cells
  • PD98059
  • Renal acidification
  • Src kinase
  • c-fos

ASJC Scopus subject areas

  • Nephrology


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