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
Olivier BlanchardAndrea Huwiler

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 t...Continue Reading

References

Jan 1, 1999·Bioorganic & Medicinal Chemistry Letters·L QiaoS Spiegel
Aug 2, 2001·American Journal of Kidney Diseases : the Official Journal of the National Kidney Foundation·S TangK N Lai
Jan 5, 2002·Physiological Reviews·Søren NielsenMark A Knepper
Feb 14, 2002·Kidney International·Alan S Verkman, Baoxue Yang
Apr 6, 2002·American Journal of Physiology. Renal Physiology·Hideki YokoiKazuwa Nakao
Jul 2, 2003·The Journal of Biological Chemistry·Hong LiuSarah Spiegel
Sep 5, 2003·The Journal of Biological Chemistry·Nobuaki IgarashiShun-ichi Nakamura
Jun 12, 2004·American Journal of Physiology. Heart and Circulatory Physiology·Xi-Lin ChenCharles Kunsch
Nov 7, 2006·Prostaglandins & Other Lipid Mediators·Helmut SchmidtGerd Geisslinger
Jan 24, 2007·Naunyn-Schmiedeberg's Archives of Pharmacology·Regina AlemanyDagmar Meyer Zu Heringdorf
Feb 22, 2007·The Journal of Biological Chemistry·Nitai C HaitSarah Spiegel
Apr 25, 2008·American Journal of Physiology. Renal Physiology·Weidong WangRobert W Schrier
Jan 24, 2009·The International Journal of Biochemistry & Cell Biology·Andreas BillichThomas Baumruker
Jun 18, 2009·The Journal of Biological Chemistry·Naoki KobayashiTsuyoshi Nishi
Jun 26, 2009·American Journal of Physiology. Renal Physiology·Hyunjin NohHi Bahl Lee
Dec 19, 2009·Journal of the American Society of Nephrology : JASN·Youhua Liu
Jan 12, 2010·The Journal of Pharmacology and Experimental Therapeutics·Kevin J FrenchCharles D Smith
Oct 21, 2010·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Graham M StrubSarah Spiegel
Mar 4, 2011·The Journal of Clinical Investigation·Wilhelm KrizMichel Le Hir
Mar 13, 2012·The Journal of Clinical Investigation·Shigetomo FukuharaNaoki Mochizuki
Mar 23, 2012·Kidney International·Ivica GrgicJoseph V Bonventre
Jul 18, 2012·Biochimica Et Biophysica Acta·Nigel J PyneSusan Pyne
Aug 15, 2012·Biochimica Et Biophysica Acta·Stephanie SchwalmAndrea Huwiler
Nov 28, 2012·FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology·Masayuki NagahashiSarah Spiegel
Dec 15, 2012·Journal of Molecular and Cellular Cardiology·Arkady RutkovskiyKåre-Olav Stensløkken
Jun 25, 2013·Basic & Clinical Pharmacology & Toxicology·Stephanie SchwalmAndrea Huwiler

❮ Previous
Next ❯

Citations

Apr 18, 2020·PloS One·Eva Nora BukoszaChristoph A Gebeshuber
Oct 17, 2018·International Journal of Molecular Sciences·Burkhard Kleuser
Dec 1, 2020·Cellular Signalling·Chiara DonatiPaola Bruni
Jan 28, 2021·Fertility and Sterility·Caterina BernacchioniFelice Petraglia
Jul 9, 2021·Circulation Research·Andrea Huwiler, Josef Pfeilschifter

❮ Previous
Next ❯

Methods Mentioned

BETA
confocal microscopy
glycosylation
ELISA
electrophoresis
Assay

Software Mentioned

Rad CFX Manager
Bio

Related Concepts

Related Feeds

Anti-inflammatory Treatments

A drug or substance that reduces inflammation (redness, swelling, and pain) in the body. Anti-inflammatory agents block certain substances in the body that cause inflammation and swelling. Discover the latest research on anti-inflammatory treatments here