Targeting Glycosphingolipid Metabolism to Treat Kidney Disease

The enhanced expression of glucosylceramide-based glycosphingolipids (GSLs) is a hallmark of many forms of renal disease including diabetic nephropathy, polycystic kidney disease and renal cell carcinoma. A common feature of each of these renal disorders is the preference metabolism via aerobic glycolysis. While aerobic glycolysis is an inefficient way to generate ATP, aerobic glycolysis promotes the formation of substrates important for the production of biomass, including lipids, amino acids and nucleotides, through the pentose phosphate pathway. Two products that are essential for the synthesis of glucosylceramide and more complex GSLs are generated through the pentose phosphate pathway. These products are reducing equivalents in the form of NADPH and UDP-glucose. In experimental models of each of these disorders, inhibition of glucosylceramide synthase with eliglustat or related analogues reverses the disease phenotype suggesting that blocking GSL synthesis should be explored as a potential treatment strategy.