| First Author | Shen Y | Year | 2015 |
| Journal | J Cell Sci | Volume | 128 |
| Issue | 19 | Pages | 3621-30 |
| PubMed ID | 26272921 | Mgi Jnum | J:233394 |
| Mgi Id | MGI:5784586 | Doi | 10.1242/jcs.171876 |
| Citation | Shen Y, et al. (2015) FoxO1 inhibits transcription and membrane trafficking of epithelial Na+ channel. J Cell Sci 128(19):3621-30 |
| abstractText | The epithelial Na(+) channel (ENaC), regulated by insulin, is of fundamental importance in the control of Na(+) reabsorption in the distal nephron. The potential role of Forkhead box O1 (FoxO1), downstream of insulin signaling, in the regulation of ENaC remains to be investigated. Here, we found that the overexpression of a constitutively active form of FoxO1 (ADA-FoxO1) suppressed the mRNA level of the ENaC alpha subunit (alpha-ENaC; also known as SCCN1A) and the apical density of ENaC in mouse cortical collecting duct (mCCD) cells. Conversely, knockdown of FoxO1 increased the apical membrane levels of alpha-ENaC and Na(+) transport under basal conditions. Insulin elevated alpha-ENaC expression and induced FoxO1 phosphorylation; however, the increase in alpha-ENaC and phosphorylated FoxO1 expression observed with insulin treatment was blunted approximately 60% in cells expressing ADA-FoxO1. Moreover, insulin induced the interaction between phosphorylated FoxO1 and 14-3-3epsilon, indicating that FoxO1 phosphorylation promotes ENaC membrane trafficking by binding to 14-3-3epsilon. FoxO1 also suppressed activity of the alpha-ENaC promoter, and the putative FoxO1 target site is located in the -500 to -200 nt region of the alpha-ENaC promoter. These findings indicate that FoxO1 is a key negative regulatory factor in the insulin-dependent control of ENaC expression and forward trafficking in mCCD epithelia. |
