Transforming growth factor-beta2 upregulates sphingosine kinase-1 activity, which in turn attenuates the fibrotic response to TGF-beta2 by impeding CTGF expression

Kidney Int. 2009 Oct;76(8):857-67. doi: 10.1038/ki.2009.297. Epub 2009 Aug 5.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Albuminuria / enzymology
  • Albuminuria / etiology
  • Animals
  • Cell Line
  • Connective Tissue Growth Factor / metabolism*
  • Diabetes Mellitus, Experimental / complications*
  • Diabetes Mellitus, Experimental / enzymology
  • Diabetes Mellitus, Experimental / pathology
  • Diabetic Nephropathies / enzymology*
  • Diabetic Nephropathies / etiology
  • Diabetic Nephropathies / pathology
  • Down-Regulation
  • Fibrosis
  • Gene Expression Regulation, Enzymologic
  • Humans
  • Lysophospholipids / metabolism*
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Knockout
  • Mutation
  • Phosphotransferases (Alcohol Group Acceptor) / antagonists & inhibitors
  • Phosphotransferases (Alcohol Group Acceptor) / deficiency
  • Phosphotransferases (Alcohol Group Acceptor) / genetics
  • Phosphotransferases (Alcohol Group Acceptor) / metabolism*
  • Podocytes / drug effects
  • Podocytes / enzymology*
  • Podocytes / pathology
  • Promoter Regions, Genetic
  • Protein Kinase Inhibitors / pharmacology
  • RNA Interference
  • RNA, Messenger / metabolism
  • Smad4 Protein / genetics
  • Smad4 Protein / metabolism
  • Sphingosine / analogs & derivatives*
  • Sphingosine / metabolism
  • Time Factors
  • Transforming Growth Factor beta1 / metabolism
  • Transforming Growth Factor beta2 / metabolism*
  • Up-Regulation


  • CCN2 protein, human
  • CCN2 protein, mouse
  • Lysophospholipids
  • Protein Kinase Inhibitors
  • RNA, Messenger
  • SMAD4 protein, human
  • Smad4 Protein
  • Transforming Growth Factor beta1
  • Transforming Growth Factor beta2
  • Connective Tissue Growth Factor
  • sphingosine 1-phosphate
  • Phosphotransferases (Alcohol Group Acceptor)
  • sphingosine kinase
  • Sphingosine