Targeting the Sphingosine Kinase/Sphingosine 1‐Phosphate Pathway to Treat Chronic Inflammatory Kidney Diseases

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.