PMID- 20375982
OWN - NLM
STAT- MEDLINE
DCOM- 20100823
LR  - 20220311
IS  - 1523-1755 (Electronic)
IS  - 0085-2538 (Linking)
VI  - 77
IP  - 10
DP  - 2010 May
TI  - Glucocorticoids protect renal mesangial cells from apoptosis by increasing 
      cellular sphingosine-1-phosphate.
PG  - 870-9
LID - 10.1038/ki.2010.62 [doi]
AB  - 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.
FAU - Forster, Ankathrin
AU  - Forster A
AD  - Klinikum der Johann Wolfgang Goethe-Universitat, Frankfurt am Main, Germany.
FAU - Emmler, Tanja
AU  - Emmler T
FAU - Schwalm, Stephanie
AU  - Schwalm S
FAU - Ebadi, Mahsa
AU  - Ebadi M
FAU - Heringdorf, Dagmar Meyer Zu
AU  - Heringdorf DM
FAU - Nieuwenhuis, Barbara
AU  - Nieuwenhuis B
FAU - Kleuser, Burkhardt
AU  - Kleuser B
FAU - Huwiler, Andrea
AU  - Huwiler A
FAU - Pfeilschifter, Josef
AU  - Pfeilschifter J
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20100310
PL  - United States
TA  - Kidney Int
JT  - Kidney international
JID - 0323470
RN  - 0 (Glucocorticoids)
RN  - 0 (Lysophospholipids)
RN  - 0 (RNA, Messenger)
RN  - 0 (Sphingolipids)
RN  - 26993-30-6 (sphingosine 1-phosphate)
RN  - 320T6RNW1F (Mifepristone)
RN  - 7S5I7G3JQL (Dexamethasone)
RN  - EC 2.7.1.- (Phosphotransferases (Alcohol Group Acceptor))
RN  - EC 2.7.1.- (sphingosine kinase)
RN  - EC 3.5.1.23 (Neutral Ceramidase)
RN  - NGZ37HRE42 (Sphingosine)
SB  - IM
CIN - Kidney Int. 2010 May;77(10):843-5. PMID: 20431574
MH  - Animals
MH  - Apoptosis/*drug effects/genetics/*physiology
MH  - Cell Differentiation/drug effects/genetics
MH  - Cells/metabolism
MH  - Dexamethasone/*pharmacology
MH  - Fibroblasts/metabolism
MH  - Glucocorticoids/genetics/*pharmacology
MH  - Lysophospholipids
MH  - Mesangial Cells/metabolism
MH  - Mice
MH  - Mice, Inbred C57BL
MH  - Mice, Mutant Strains
MH  - Mifepristone/pharmacology
MH  - Neutral Ceramidase
MH  - Phosphotransferases (Alcohol Group Acceptor)
MH  - RNA, Messenger/genetics/metabolism/pharmacology
MH  - Rats
MH  - Response Elements/drug effects
MH  - Sphingolipids/genetics/pharmacology
MH  - Sphingosine/analogs & derivatives
EDAT- 2010/04/09 06:00
MHDA- 2010/08/24 06:00
CRDT- 2010/04/09 06:00
PHST- 2010/04/09 06:00 [entrez]
PHST- 2010/04/09 06:00 [pubmed]
PHST- 2010/08/24 06:00 [medline]
AID - S0085-2538(15)54155-0 [pii]
AID - 10.1038/ki.2010.62 [doi]
PST - ppublish
SO  - Kidney Int. 2010 May;77(10):870-9. doi: 10.1038/ki.2010.62. Epub 2010 Mar 10.