Document Detail


Glucocorticoids protect renal mesangial cells from apoptosis by increasing cellular sphingosine-1-phosphate.
MedLine Citation:
PMID:  20375982     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Neutral ceramidase (NCDase) and sphingosine kinases (SphKs) are key enzymes regulating cellular sphingosine-1-phosphate (S1P) levels. In this study we found that stress factor-induced apoptosis of rat renal mesangial cells was significantly reduced by dexamethasone treatment. Concomitantly, dexamethasone increased cellular S1P levels, suggesting an activation of sphingolipid-metabolizing enzymes. The cell-protective effect of glucocorticoids was reversed by a SphK inhibitor, was completely absent in SphK1-deficient cells, and was associated with upregulated mRNA and protein expression of NCDase and SphK1. Additionally, in vivo experiments in mice showed that dexamethasone also upregulated SphK1 mRNA and activity, and NCDase protein expression in the kidney. Fragments (2285, 1724, and 1126 bp) of the rat NCDase promoter linked to a luciferase reporter were transfected into rat kidney fibroblasts and mesangial cells. There was enhanced NCDase promoter activity upon glucocorticoids treatment that was abolished by the glucocorticoid receptor antagonist RU-486. Single and double mutations of the two putative glucocorticoid response element sites within the promoter reduced the dexamethasone effect, suggesting that both glucocorticoid response elements are functionally active and required for induction. Our study shows that glucocorticoids exert a protective effect on stress-induced mesangial cell apoptosis in vitro and in vivo by upregulating NCDase and SphK1 expression and activity, resulting in enhanced levels of the protective lipid second messenger S1P.
Authors:
Ankathrin Förster; Tanja Emmler; Stephanie Schwalm; Mahsa Ebadi; Dagmar Meyer Zu Heringdorf; Barbara Nieuwenhuis; Burkhardt Kleuser; Andrea Huwiler; Josef Pfeilschifter
Publication Detail:
Type:  Journal Article; Research Support, Non-U.S. Gov't     Date:  2010-03-10
Journal Detail:
Title:  Kidney international     Volume:  77     ISSN:  1523-1755     ISO Abbreviation:  Kidney Int.     Publication Date:  2010 May 
Date Detail:
Created Date:  2010-04-30     Completed Date:  2010-08-23     Revised Date:  -    
Medline Journal Info:
Nlm Unique ID:  0323470     Medline TA:  Kidney Int     Country:  United States    
Other Details:
Languages:  eng     Pagination:  870-9     Citation Subset:  IM    
Affiliation:
Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany.
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MeSH Terms
Descriptor/Qualifier:
Animals
Apoptosis / drug effects*,  genetics,  physiology*
Cell Differentiation / drug effects,  genetics
Cells / metabolism
Dexamethasone / pharmacology*
Fibroblasts / metabolism
Glucocorticoids / genetics,  pharmacology*
Lysophospholipids
Mesangial Cells / metabolism
Mice
Mice, Inbred C57BL
Mice, Mutant Strains
Mifepristone / pharmacology
Neutral Ceramidase
Phosphotransferases (Alcohol Group Acceptor)
RNA, Messenger / genetics,  metabolism,  pharmacology
Rats
Response Elements / drug effects
Sphingolipids / genetics,  pharmacology
Sphingosine / analogs & derivatives
Chemical
Reg. No./Substance:
0/Glucocorticoids; 0/Lysophospholipids; 0/RNA, Messenger; 0/Sphingolipids; 123-78-4/Sphingosine; 26993-30-6/sphingosine 1-phosphate; 50-02-2/Dexamethasone; 84371-65-3/Mifepristone; EC 2.7.1.-/Phosphotransferases (Alcohol Group Acceptor); EC 2.7.1.-/sphingosine kinase; EC 3.5.1.23/Neutral Ceramidase
Comments/Corrections
Comment In:
Kidney Int. 2010 May;77(10):843-5   [PMID:  20431574 ]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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