Sphingolipid signaling in renal fibrosis

Over the last decade, various sphingolipid subspecies have gained increasing attention as important signaling molecules that regulate a multitude of physiological and pathophysiological processes including inflammation and tissue remodeling. These mediators include ceramide, sphingosine 1-phosphate (S1P), the cerebroside glucosylceramide, lactosylceramide, and the gangliosides GM3 and Gb3. These lipids have been shown to accumulate in various chronic kidney diseases that typically end in renal fibrosis and ultimately renal failure. This review will summarize the effects and contributions of those enzymes that regulate the generation and interconversion of these lipids, notably the acid sphingomyelinase, the acid sphingomyelinase-like protein SMPDL3B, the sphingosine kinases, the S1P lyase, the glucosylceramide synthase, the GM3 synthase, and the α-galactosidase A, to renal fibrotic diseases. Strategies of manipulating these enzymes for therapeutic purposes and the impact of existing drugs on renal pathologies will be discussed.