Transforming growth factor-beta2 upregulates sphingosine kinase-1 activity, which in turn attenuates the fibrotic response to TGF-beta2 by impeding CTGF expression.
Transforming growth factor-beta2 (TGF-beta2) stimulates the expression of pro-fibrotic connective tissue growth factor (CTGF) during the course of renal disease. Because sphingosine kinase-1 (SK-1) activity is also upregulated by TGF-beta, we studied its effect on CTGF expression and on the development of renal fibrosis. When TGF-beta2 was added to an immortalized human podocyte cell line we found that it activated the promoter of SK-1, resulting in upregulation of its mRNA and protein expression. Further, depletion of SK-1 by small interfering RNA or its pharmacological inhibition led to accelerated CTGF expression in the podocytes. Over-expression of SK-1 reduced CTGF induction, an effect mediated by intracellular sphingosine-1-phosphate. In vivo, SK-1 expression was also increased in the podocytes of kidney sections of patients with diabetic nephropathy when compared to normal sections of kidney obtained from patients with renal cancer. Similarly, in a mouse model of streptozotocin-induced diabetic nephropathy, SK-1 and CTGF were upregulated in podocytes. In SK-1 deficient mice, exacerbation of disease was detected by increased albuminuria and CTGF expression when compared to wild-type mice. Thus, SK-1 activity has a protective role in the fibrotic process and its deletion or inhibition aggravates fibrotic disease.
Ren
Shuyu
S
Institute of Pharmacology, University of Bern, Switzerland.
Babelova
Andrea
A
Moreth
Kristin
K
Xin
Cuiyan
C
Eberhardt
Wolfgang
W
Doller
Anke
A
Pavenstädt
Hermann
H
Schaefer
Liliana
L
Pfeilschifter
Josef
J
Huwiler
Andrea
A
D000419:Albuminuria / Q000201:enzymology / Q000209:etiology; D000818:Animals; D002460:Cell Line; D055513:Connective Tissue Growth Factor / Q000378:metabolism*; D003921:Diabetes Mellitus, Experimental / Q000150:complications* / Q000201:enzymology / Q000473:pathology; D003928:Diabetic Nephropathies / Q000201:enzymology* / Q000209:etiology / Q000473:pathology; D015536:Down-Regulation; D005355:Fibrosis; D015971:Gene Expression Regulation, Enzymologic; D006801:Humans; D008246:Lysophospholipids / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009154:Mutation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D050199:Podocytes / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D011401:Promoter Regions, Genetic; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D012333:RNA, Messenger / Q000378:metabolism; D051901:Smad4 Protein / Q000235:genetics / Q000378:metabolism; D013110:Sphingosine / Q000031:analogs & derivatives* / Q000378:metabolism; D013997:Time Factors; D053773:Transforming Growth Factor beta1 / Q000378:metabolism; D053781:Transforming Growth Factor beta2 / Q000378:metabolism*; D015854:Up-Regulation; D000099157:Sphingosine Kinase
D055513:Connective Tissue Growth Factor; D008246:Lysophospholipids; D017853:Phosphotransferases (Alcohol Group Acceptor); D047428:Protein Kinase Inhibitors; D012333:RNA, Messenger; D051901:Smad4 Protein; D013110:Sphingosine; D053773:Transforming Growth Factor beta1; D053781:Transforming Growth Factor beta2; D000099157:Sphingosine Kinase; C526317:CCN2 protein, human; C526318:CCN2 protein, mouse; C497796:SMAD4 protein, human; C060506:sphingosine 1-phosphate