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Downregulation of the S1P Transporter Spinster Homology Protein 2 (Spns2) Exerts an Anti-Fibrotic and Anti-Inflammatory Effect in Human Renal Proximal Tubular Epithelial Cells.

Authors
  • Blanchard, Olivier1
  • Stepanovska, Bisera2
  • Starck, Manuel3
  • Erhardt, Martin4
  • Römer, Isolde5
  • Meyer Zu Heringdorf, Dagmar6
  • Pfeilschifter, Josef7
  • Zangemeister-Wittke, Uwe8
  • Huwiler, Andrea9
  • 1 Institute of Pharmacology, University of Bern, Inselspital, INO-F, CH-3010 Bern, Switzerland. [email protected] , (Switzerland)
  • 2 Institute of Pharmacology, University of Bern, Inselspital, INO-F, CH-3010 Bern, Switzerland. [email protected] , (Switzerland)
  • 3 Institute of Pharmacology, University of Bern, Inselspital, INO-F, CH-3010 Bern, Switzerland. [email protected] , (Switzerland)
  • 4 Institute of Pharmacology, University of Bern, Inselspital, INO-F, CH-3010 Bern, Switzerland. [email protected] , (Switzerland)
  • 5 Institute of General Pharmacology and Toxicology, University Hospital Frankfurt am Main, Goethe-University, Theodor-Stern Kai 7, D-60590 Frankfurt am Main, Germany. [email protected] , (Germany)
  • 6 Institute of General Pharmacology and Toxicology, University Hospital Frankfurt am Main, Goethe-University, Theodor-Stern Kai 7, D-60590 Frankfurt am Main, Germany. [email protected] , (Germany)
  • 7 Institute of General Pharmacology and Toxicology, University Hospital Frankfurt am Main, Goethe-University, Theodor-Stern Kai 7, D-60590 Frankfurt am Main, Germany. [email protected] , (Germany)
  • 8 Institute of Pharmacology, University of Bern, Inselspital, INO-F, CH-3010 Bern, Switzerland. [email protected] , (Switzerland)
  • 9 Institute of Pharmacology, University of Bern, Inselspital, INO-F, CH-3010 Bern, Switzerland. [email protected] , (Switzerland)
Type
Published Article
Journal
International Journal of Molecular Sciences
Publisher
MDPI AG
Publication Date
May 17, 2018
Volume
19
Issue
5
Identifiers
DOI: 10.3390/ijms19051498
PMID: 29772789
Source
Medline
Keywords
License
Unknown

Abstract

Sphingosine kinase (SK) catalyses the formation of sphingosine 1-phosphate (S1P), which acts as a key regulator of inflammatory and fibrotic reactions, mainly via S1P receptor activation. Here, we show that in the human renal proximal tubular epithelial cell line HK2, the profibrotic mediator transforming growth factor β (TGFβ) induces SK-1 mRNA and protein expression, and in parallel, it also upregulates the expression of the fibrotic markers connective tissue growth factor (CTGF) and fibronectin. Stable downregulation of SK-1 by RNAi resulted in the increased expression of CTGF, suggesting a suppressive effect of SK-1-derived intracellular S1P in the fibrotic process, which is lost when SK-1 is downregulated. In a further approach, the S1P transporter Spns2, which is known to export S1P and thereby reduces intracellular S1P levels, was stably downregulated in HK2 cells by RNAi. This treatment decreased TGFβ-induced CTGF and fibronectin expression, and it abolished the strong induction of the monocyte chemotactic protein 1 (MCP-1) by the pro-inflammatory cytokines tumor necrosis factor (TNF)α and interleukin (IL)-1β. Moreover, it enhanced the expression of aquaporin 1, which is an important water channel that is expressed in the proximal tubules, and reverted aquaporin 1 downregulation induced by IL-1β/TNFα. On the other hand, overexpression of a Spns2-GFP construct increased S1P secretion and it resulted in enhanced TGFβ-induced CTGF expression. In summary, our data demonstrate that in human renal proximal tubular epithelial cells, SK-1 downregulation accelerates an inflammatory and fibrotic reaction, whereas Spns2 downregulation has an opposite effect. We conclude that Spns2 represents a promising new target for the treatment of tubulointerstitial inflammation and fibrosis.

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