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Targeting the Sphingosine Kinase/Sphingosine 1‐Phosphate Pathway to Treat Chronic Inflammatory Kidney Diseases
Author(s) -
Schwalm Stephanie,
Pfeilschifter Josef,
Huwiler Andrea
Publication year - 2014
Publication title -
basic and clinical pharmacology and toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.805
H-Index - 90
eISSN - 1742-7843
pISSN - 1742-7835
DOI - 10.1111/bcpt.12103
Subject(s) - sphingosine kinase 1 , sphingosine , glomerulonephritis , kidney disease , sphingosine 1 phosphate , sphingosine kinase , medicine , inflammation , fibrosis , pharmacology , kidney , sphingolipid , focal segmental glomerulosclerosis , acute kidney injury , cancer research , immunology , receptor , biology , microbiology and biotechnology
Abstract Chronic kidney diseases including glomerulonephritis are often accompanied by acute or chronic inflammation that leads to an increase in extracellular matrix ( ECM ) production and subsequent glomerulosclerosis. Glomerulonephritis is one of the leading causes for end‐stage renal failure with high morbidity and mortality, and there are still only a limited number of drugs for treatment available. In this M ini R eview, we discuss the possibility of targeting sphingolipids, specifically the sphingosine kinase 1 ( S ph K 1) and sphingosine 1‐phosphate ( S 1 P ) pathway, as new therapeutic strategy for the treatment of glomerulonephritis, as this pathway was demonstrated to be dysregulated under disease conditions. Sphingosine 1‐phosphate is a multifunctional signalling molecule, which was shown to influence several hallmarks of glomerulonephritis including mesangial cell proliferation, renal inflammation and fibrosis. Most importantly, the site of action of S 1 P determines the final effect on disease progression. Concerning renal fibrosis, extracellular S 1 P acts pro‐fibrotic via activation of cell surface S 1 P receptors, whereas intracellular S 1 P was shown to attenuate the fibrotic response. Interference with S 1 P signalling by treatment with FTY 720, an S 1 P receptor modulator, resulted in beneficial effects in various animal models of chronic kidney diseases. Also, sonepcizumab, a monoclonal anti‐ S 1 P antibody that neutralizes extracellular S 1 P , and a S 1 P ‐degrading recombinant S 1 P lyase are promising new strategies for the treatment of glomerulonephritis. In summary, especially due to the bifunctionality of S 1 P , the S ph K 1/ S 1 P pathway provides multiple target sites for the treatment of chronic kidney diseases.