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Thiazolidinedione‐dependent activation of sphingosine kinase 1 causes an anti‐fibrotic effect in renal mesangial cells
Author(s) -
Koch A,
Völzke A,
Wünsche C,
Meyer zu Heringdorf D,
Huwiler A,
Pfeilschifter J
Publication year - 2012
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/j.1476-5381.2012.01824.x
Subject(s) - ctgf , sphingosine kinase 1 , troglitazone , thiazolidinedione , sphingosine , mesangial cell , intracellular , sphingosine kinase , endocrinology , medicine , chemistry , sphingosine 1 phosphate , microbiology and biotechnology , growth factor , peroxisome proliferator activated receptor , biology , receptor , kidney , type 2 diabetes , diabetes mellitus
BACKGROUND AND PURPOSE 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. EXPERIMENTAL APPROACH 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. KEY 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. CONCLUSION AND IMPLICATIONS 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.