C-peptide stimulates Na+,K+-ATPase via activation of ERK1/2 MAP kinases in human renal tubular cells

Research output: Contribution to journalArticle


Proinsulin-connecting peptide (C-peptide) exerts physiological effects partially via stimulation of Na+, K+-ATPase. We determined the molecular mechanism by which C-peptide stimulates Na+,K +-ATPase in primary human renal tubular cells (HRTCs). Incubation of the cells with 5 nM human C-peptide at 37°C for 10 min stimulated 86Rb+ uptake by 40% (p<0.01). The carboxy-terminal pentapeptide was found to elicit 57% of the activity of the intact molecule. In parallel with ouabain-sensitive 86Rb+ uptake, C-peptide increased α subunit phosphorylation and basolateral membrane (BLM) abundance of the Na+,K+-ATPase α1 and β1 subunits. The increase in BLM abundance of the Na +,K+-ATPase α1 and β1 subunits was accompanied by depletion of α1 and β1 subunits from the endosomal compartments. C-peptide action on Na+,K+-ATPase was ERK1/2-dependent in HRTCs. C-peptide-stimulated Na+,K+-ATPase activation, phosphorylation of α1-subunit and translocation of α1 and β1 subunits to the BLM were abolished by a MEK1/2 inhibitor (20 μM PD98059). C-peptide stimulation of 86Rb+ uptake was also abolished by preincubation of HRTCs with an inhibitor of PKC (1 μM GF109203X). C-peptide stimulated phosphorylation of human Na+,K+-ATPase α subunit on Thr-Pro amino acid motifs, which form specific ERK substrates. In conclusion, C-peptide stimulates sodium pump activity via ERK1/2-induced phosphorylation of Thr residues on the α subunit of Na+,K+-ATPase.


  • Z. Zhong
  • O. Kotova
  • A. Davidescu
  • I. Ehrén
  • K. Ekberg
  • H. Jörnvall
  • J. Wahren
  • A. V. Chibalin
External organisations
  • Karolinska Institutet
Research areas and keywords

Subject classification (UKÄ) – MANDATORY

  • Cell and Molecular Biology


  • C-peptide, Kidney, MAP kinase, Na pump, PKC, Sodium pump
Original languageEnglish
Pages (from-to)2782-2790
JournalCellular and Molecular Life Sciences
Issue number21
Publication statusPublished - 2004 Nov 1
Publication categoryResearch
Externally publishedYes