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This Article Full Text Full Text (PDF) All Versions of this Article: 293/4/F1178    most recent 00153.2007v1 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 Web of Science Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Web of Science (5) Citing Articles via Google Scholar Google Scholar Articles by Bao, H.-F. Articles by Ma, H.-P. Search for Related Content PubMed PubMed Citation Articles by Bao, H.-F. Articles by Ma, H.-P.

Ceramide mediates inhibition of the renal epithelial sodium channel by tumor necrosis factor- through protein kinase C

¹Department of Physiology, Emory University School of Medicine, Atlanta, Georgia; ²Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, South Carolina; and ³Department of Medicine, Division of Nephrology, University of Alabama at Birmingham, Birmingham, Alabama

Submitted 2 April 2007 ; accepted in final form 17 July 2007

To determine whether ceramide mediates regulation of the renal epithelial sodium channel (ENaC) by tumor necrosis factor- (TNF-), confocal microscopy and patch-clamp experiments were performed in A6 distal nephron cells. We found that TNF- (100 ng/ml) had no effect on ENaC activity and ceramide level when the cells were grown in the presence of aldosterone, but significantly inhibited ENaC and induced ceramide production after the cells were pretreated with LY 294002, an inhibitor of phosphatidylinositol 3-kinase, for 24 h. The inhibition of ENaC induced by TNF- was mimicked by exogenous sphingomyelinase (0.1 U/ml) and C₂-ceramide (50 µM), but neither C₂-dihydroceramide, a membrane-impermeable analog of C₂-ceramide, nor choline, and abolished by pretreatment with GF109203X, a protein kinase C (PKC) inhibitor. C₂-ceramide failed to affect ENaC in the cells pretreated with GF109203X, but not in the cells pretreated with PD-98059, a mitogen-activated protein kinase kinase inhibitor. C₂-ceramide induced the externalization of phosphatidylserine (PS) in control A6 cells, but not in the cells pretreated with GF109203X. Together with our previous finding that cytosolic PS maintains ENaC activity in A6 cells, these data suggest that ceramide mediates TNF- inhibition of the renal ENaC via a pathway associated with PKC-dependent externalization of PS.

A6 cells; single-channel recordings; confocal microscopy; sphingomyelinase; C₂-ceramide; phosphatidylserine

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