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1 Department of Cell Physiology, Universite Libre de Bruxelles, Brussels, Belgium
2 Interdisciplinary Research Institute (RIBHM), Universite Libre de Bruxelles, Brussels, Belgium
3 Laboratory of Histology, Neuroanatomy and Neuropathology, Universite Libre de Bruxelles, Brussels, Belgium
* To whom correspondence should be addressed. E-mail: renbeau{at}ulb.ac.be.
Insulin stimulates sodium transport across A6 epithelial cell monolayers. Activation of phosphatidylinositol 3-kinase (PI 3-kinase) was suggested as an early step in the insulin-stimulated sodium reabsorption (Record et al., Am J Physiol 274: E611-7, 1998). To establish that the stimulation of the PI 3-kinase signalling cascade is causing stimulation of apical ENaC, we added permeant forms of phosphatidylinositol (PI) phosphate (P) derivatives complexed with a histone carrier to A6 epithelium. Only PIP3 and PI(3,4)P2 but not PI(4,5)P2 stimulated sodium transport, although each of them penetrated into A6 cell monolayers as assessed using fluorescent permeant phosphoinositides derivatives. By Western blot analysis of A6 cell extracts, the inositol 3-phosphatase, PTEN and the protein kinase B, PKB were both detected. To further establish that the stimulation of sodium transport induced by insulin is related to PIP3 levels, we transfected A6 cells with human PTEN cDNA and observed a 30% decrease in the natriferic effect of insulin. Similarly the increase in sodium transport observed by addition of permeant PIP3 was also reduced by 30% in PTEN overexpressing cells. PKB, a main downstream effector of PI 3-kinase was phosphorylated at both Thr 308 and Ser 473 residues upon insulin stimulation of A6 cell monolayer. PKB phosphorylation in response to insulin stimulation was reduced in PTEN overexpressing cells. Permeant PIP3 also increased PKB phosphorylation. Taken together, the present results establish that the D-3 phosphorylated phosphoinositides PIP3 and PI(3,4)P2 mediate the effect of insulin on sodium transport across A6 cell monolayers.
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