C-peptide stimulates Na+, K+-ATPase via activation of ERK1/2 MAP kinases in human renal tubular cells |
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Authors: | Z.?Zhong,O.?Kotova,A.?Davidescu,I.?Ehrén,K.?Ekberg,H.?J?rnvall,J.?Wahren,A.?V.?Chibalin author-information" > author-information__contact u-icon-before" > mailto:alexander.Chibalin@kirurgi.ki.se" title=" alexander.Chibalin@kirurgi.ki.se" itemprop=" email" data-track=" click" data-track-action=" Email author" data-track-label=" " >Email author |
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Affiliation: | (1) Section of Clinical Physiology, Department of Surgical Sciences, Karolinska Institutet, 17177 Stockholm, Sweden;(2) Section of Integrative Physiology, Department of Surgical Sciences, Karolinska Institutet, von Eulers väg 4, 4 tr, 17177 Stockholm, Sweden;(3) Section of Urology, Department of Surgical Sciences, Karolinska Institutet, 17177 Stockholm, Sweden;(4) Department of Medical Biochemistry and Biophysics, Karolinska Institutet, 17177 Stockholm, Sweden |
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Abstract: | 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 subunit phosphorylation and basolateral membrane (BLM) abundance of the Na+, K+-ATPase 1 and 1 subunits. The increase in BLM abundance of the Na+, K+-ATPase 1 and 1 subunits was accompanied by depletion of 1 and 1 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 1-subunit and translocation of 1 and 1 subunits to the BLM were abolished by a MEK1/2 inhibitor (20 M PD98059). C-peptide stimulation of 86Rb+ uptake was also abolished by preincubation of HRTCs with an inhibitor of PKC (1 M GF109203X). C-peptide stimulated phosphorylation of human Na+, K+-ATPase 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 subunit of Na+, K+-ATPase.Received 15 June 2004; received after revision 14 September 2004; accepted 14 September 2004 |
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Keywords: | Na pump sodium pump C-peptide kidney MAP kinase PKC |
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