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Targeting Glycosphingolipid Metabolism to Treat Kidney Disease

James A Shayman1

  • 1Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Mich., USA.

Nephron
|March 9, 2016
PubMed

Insights

Enhanced glycosphingolipid (GSL) expression drives renal diseases like diabetic nephropathy. Inhibiting GSL synthesis, a process fueled by aerobic glycolysis, may reverse kidney disease phenotypes.

Area of Science:

  • Biochemistry
  • Nephrology
  • Metabolic pathways

Background:

  • Enhanced expression of glucosylceramide-based glycosphingolipids (GSLs) is a hallmark of various renal diseases, including diabetic nephropathy, polycystic kidney disease, and renal cell carcinoma.
  • These renal disorders share a common metabolic feature: a preference for aerobic glycolysis.

Purpose of the Study:

  • To investigate the role of aerobic glycolysis and its downstream products in the pathogenesis of renal diseases.
  • To explore the therapeutic potential of inhibiting glucosylceramide synthase in experimental models of renal disorders.

Main Methods:

  • Analysis of metabolic pathways, specifically aerobic glycolysis and the pentose phosphate pathway, in the context of renal disease.
  • Experimental inhibition of glucosylceramide synthase using eliglustat and related analogues in preclinical models.

Main Results:

  • Aerobic glycolysis, while inefficient for ATP production, supports biomass synthesis through the pentose phosphate pathway, generating essential GSL precursors like NADPH and UDP-glucose.
  • Inhibition of glucosylceramide synthase reversed disease phenotypes in experimental models of diabetic nephropathy, polycystic kidney disease, and renal cell carcinoma.

Conclusions:

  • The pentose phosphate pathway, fueled by aerobic glycolysis, provides essential substrates for GSL synthesis, contributing to renal disease pathogenesis.
  • Targeting glucosylceramide synthase represents a promising therapeutic strategy for various kidney disorders characterized by enhanced GSL expression.

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