Targeting Glucosylceramide Synthesis in the Treatment of Rare and Common Renal Disease

Abstract

Sphingolipids, including ceramides, glycosphingolipids, sphingomyelin, and sphingosine-1-phosphate, have been recognized as important molecules that regulate critical cellular functions. Although originally studied in the context of lysosomal storage diseases, the roles of these compounds in more common disorders involving metabolism, vascular disease, and aberrant growth has been the focus of recent studies, including in disorders that affect the kidneys. These efforts have led to new insights into Fabry disease, a classic disorder of lysosomal function that results in renal failure as well as in more common renal diseases including diabetic nephropathy and polycystic kidney disease. Pathways for glycosphingolipid synthesis can be targeted with orally available small-molecule inhibitors, creating new opportunities for the treatment of both rare and common kidney diseases.

Keywords: Fabry disease; Glycosphingolipids; diabetes; glucosylceramide; polycystic kidney disease; substrate reduction.