HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: 292/5/C1874    most recent 00617.2006v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in ISI Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Wang, X. Articles by Price, S. R. Search for Related Content PubMed PubMed Citation Articles by Wang, X. Articles by Price, S. R.

RECEPTORS AND SIGNAL TRANSDUCTION

Inhibition of PI3-kinase signaling by glucocorticoids results in increased branched-chain amino acid degradation in renal epithelial cells

Renal Division, Emory University, Atlanta, Georgia

Submitted 12 December 2006 ; accepted in final form 12 January 2007

Phosphatidylinositol 3-kinase(PI3K) is a pivotal enzyme involved in the control of a variety of diverse metabolic functions. Glucocorticoids have been shown to attenuate PI3K signaling in some nonrenal cell types, raising the possibility that some physiological effects of glucocorticoids in renal cells may be achieved by a similar mechanism. Therefore, we tested whether glucocorticoids affect signaling through the insulin receptor substrate (IRS)-1/PI3K/Akt signaling cascade in LLC-PK1-GR101 renal epithelial cells. Treatment of cells with dexamethasone for 24 h: 1) suppressed IRS-1-associated PI3K activity and Akt phosphorylation, 2) increased the level of the PI3K p85 regulatory subunit but not the p110 catalytic subunit, and 3) induced the phosphorylation of IRS-1 on inhibitory Ser³⁰⁷. We have previously reported that glucocorticoids increase branched-chain ketoacid dehydrogenase (BCKD) activity in LLC-PK1-GR101 cells. This response was achieved, in part, by alterations in the transcription of BCKD subunits and BCKD kinase, which inactivates the enzyme complex by phosphorylation. Therefore, we tested whether inhibition of PI3K signaling would mimick glucocorticoids by increasing branched-chain amino acid degradation. Expression of a dominant negative PI3K p85 regulatory subunit (Adp85iSH2) increased BCKD activity, and dexamethasone did not further stimulate enzyme activity. Inhibition of PI3K using LY-294002 increased the transcription of the BCKD E2 subunit but not the E1 subunit or BCKD kinase. Thus, glucocorticoids inhibit signaling through the IRS-1/PI3K/Akt pathway with a consequence of increased branched-chain amino acid catabolism.

phosphatidylinositol 3-kinase; kidney