Thiazolidinedione-dependent activation of sphingosine kinase 1 causes an anti-fibrotic effect in renal mesangial cells.
OBJECTIVE
PPARγ agonists [thiazolidinediones (TZDs)] are known to exert anti-fibrotic effects in the kidney. In addition, we previously demonstrated that sphingosine kinase 1 (SK-1) and intracellular sphingosine-1-phosphate (S1P), by reducing the expression of connective tissue growth factor (CTGF), have a protective role in the fibrotic process.


METHODS
Here, we investigated the effect of TZDs on intracellular sphingolipid levels and the transcriptional regulation of SK-1 in mesangial cells to evaluate potential novel aspects of the anti-fibrotic capacity of TZDs.


RESULTS
Stimulation with the TZDs, troglitazone and rosiglitazone, led to increased S1P levels in rat mesangial cells. This was paralleled by increased SK-1 activity as a consequence of direct effects of the TZDs on SK-1 expression. GW-9662, a PPARγ antagonist, inhibited the stimulating effect of TZDs on SK-1 mRNA and activity levels and intracellular S1P concentrations. Furthermore, SK-1 up-regulation by TZDs was functionally coupled with lower amounts of pro-fibrotic CTGF. SK-1 inhibition with SKI II almost completely abolished this effect in a dose-dependent manner. Moreover, the CTGF lowering effect of TZDs was fully blocked in MC isolated from SK-1 deficient mice (SK-1(-/-) ) as well as in glomeruli of SK-1(-/-)  mice compared with wild-type mice treated with TRO and RSG.


CONCLUSIONS
These data show that TZD-induced SK-1 up-regulation results in lower amounts of CTGF, demonstrating novel facets for the anti-fibrotic effects of this class of drugs.
Pharmazentrum frankfurt/ZAFES, Klinikum der Johann Wolfgang Goethe-Universität, Frankfurt am Main, Germany. koch@med.uni-frankfurt.de
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Koch
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Völzke
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C
Wünsche
D
D
Meyer zu Heringdorf
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Huwiler
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Pfeilschifter
D000818:Animals; D015153:Blotting, Western; D018929:Cell Culture Techniques; D002478:Cells, Cultured; D055513:Connective Tissue Growth Factor / Q000096:biosynthesis; D004789:Enzyme Activation; D005260:Female; D005355:Fibrosis; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism; D050527:Mesangial Cells / Q000187:drug effects* / Q000201:enzymology / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016297:Mutagenesis, Site-Directed; D047495:PPAR gamma / Q000819:agonists* / Q000037:antagonists & inhibitors; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D011401:Promoter Regions, Genetic; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D013110:Sphingosine / Q000031:analogs & derivatives / Q000378:metabolism; D045162:Thiazolidinediones / Q000494:pharmacology*; D015854:Up-Regulation; D000099157:Sphingosine Kinase
D055513:Connective Tissue Growth Factor; D008246:Lysophospholipids; D047495:PPAR gamma; D017853:Phosphotransferases (Alcohol Group Acceptor); D013110:Sphingosine; D045162:Thiazolidinediones; D000099157:Sphingosine Kinase; C060506:sphingosine 1-phosphate; C089946:2,4-thiazolidinedione