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

Autor: Bisera Stepanovska, Olivier Blanchard, Andrea Huwiler, Martin Erhardt, Uwe Zangemeister-Wittke, Manuel Thierry Starck, Isolde Römer, Dagmar Meyer zu Heringdorf, Josef Pfeilschifter
Jazyk: angličtina
Rok vydání: 2018
Předmět:
0301 basic medicine
sphingosine kinase 1
Sphingosine kinase
Fluorescent Antibody Technique
lcsh:Chemistry
Kidney Tubules
Proximal
Fibrosis
Sphingosine
aquaporin 1
RNA
Small Interfering
610 Medicine & health
lcsh:QH301-705.5
Spectroscopy
Cells
Cultured
biology
Chemistry
Podocytes
General Medicine
Computer Science Applications
Cell biology
Sphingosine kinase 1
Aquaporin 1
Gene Knockdown Techniques
Tumor necrosis factor alpha
RNA Interference
Anion Transport Proteins
Down-Regulation
Catalysis
Article
Inorganic Chemistry
spinster homology protein 2 (Spns2)
03 medical and health sciences
human renal proximal tubular epithelial cells
Downregulation and upregulation
fibrosis
inflammation
sphingosine 1-phosphate
CTGF
medicine
Humans
ddc:610
RNA
Messenger
Physical and Theoretical Chemistry
Molecular Biology
Inflammation
Organic Chemistry
Epithelial Cells
medicine.disease
030104 developmental biology
lcsh:Biology (General)
lcsh:QD1-999
Gene Expression Regulation
biology.protein
Lysophospholipids
Biomarkers
Transforming growth factor
Zdroj: International Journal of Molecular Sciences; Volume 19; Issue 5; Pages: 1498
International Journal of Molecular Sciences
Blanchard, Olivier; Stepanovska, Bisera; Starck, Manuel Thierry; Erhardt, Martin; Römer, Isolde; Meyer Zu Heringdorf, Dagmar; Pfeilschifter, Josef; Zangemeister-Wittke, Uwe; Huwiler, Andrea (2018). 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. International journal of molecular sciences, 19(5) Molecular Diversity Preservation International MDPI 10.3390/ijms19051498
International Journal of Molecular Sciences, Vol 19, Iss 5, p 1498 (2018)
ISSN: 1422-0067
DOI: 10.3390/ijms19051498
Popis: 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.
Databáze: OpenAIRE
Externí odkaz:
Nepřihlášeným uživatelům se plný text nezobrazuje