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Phosphatidylinositol 3,4,5-trisphosphate: an early mediator of insulin-stimulated sodium transport in A6 cells

¹Department of Cell Physiology, ²Interdisciplinary Research Institute, ³Laboratory of Histology, Neuroanatomy and Neuropathology, Université Libre de Bruxelles, Campus Erasme, 1070 Bruxelles, Belgium

Submitted 2 September 2003 ; accepted in final form 12 April 2004

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 (Ref. 35). To establish that the stimulation of the PI 3-kinase signaling cascade is causing stimulation of apical epithelial Na channel, 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 the 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.

epithelial Na⁺ channel; protein kinase B; phosphatase and TENsin homolog deleted on chromosome 10; kidney

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