Abstract
Sphingolipids are well-recognized as major players in the pathogenesis of many human diseases, including chronic kidney disease. The kidney is a very sensitive organ to alterations in sphingolipid metabolism. The critical issues to be addressed in this review relate to the role of sphingolipids and enzymes involved in sphingolipid metabolism in the pathogenesis of glomerular diseases with a special focus on podocytes, a key cellular component of the glomerular filtration barrier. Among several sphingolipids, we will highlight the role of ceramide, sphingosine, sphingosine-1-phosphate and ceramide-1-phosphate. Additionally, we will summarize the current knowledge with regard to the use of sphingolipids as therapeutic agents for the treatment of podocyte injury in kidney disease.
Highlights
Being a sophisticated and highly organized living system, mammals harbor a large number of biomolecular machineries which represent a dynamic and complex network of interconnections responsible for the effective operation, development and survivability of their body cells
We reported that rituximab, an anti-CD20 monoclonal antibody targeting B cells, binds to sphingomyelin phosphodiesterase acid-like 3b (SMPDL3b), thereby protecting podocytes from cytoskeleton disruption and apoptosis induced by treatment with sera from patients with recurrent focal segmental glomerulosclerosis (FSGS) [85]
We highlighted new research trends and scientific knowledge acquired within the past few years indicating that sphingolipids are key players contributing to the pathogenesis and progression of glomerular diseases such as diabetic kidney disease (DKD) and FSGS (Figure 2)
Summary
Being a sophisticated and highly organized living system, mammals harbor a large number of biomolecular machineries which represent a dynamic and complex network of interconnections responsible for the effective operation, development and survivability of their body cells. Our studies demonstrated that exogenous C1P treatment or podocyte-specific inhibition of SMDP3Lb results in reduced proteinuria, improves renal outcome and restores insulin receptor signaling in diabetic db/db mice [6]. Rituximab may represent a potentially effective agent for the treatment of some glomerular diseases Whether these beneficial effects are due to B lymphocyte depletion or to stabilization of SMPDL3b expression and function cannot be discerned in treated patients and requires further experimental studies with humanized mouse models. Another reported therapy targeting sphingolipids is enzyme replacement therapy (ERT), which currently represents a standard of therapy for Fabry disease, or lipid storage disease. While ERT may be a very promising therapy for the treatment of lipid storage disease, its therapeutic potential in the treatment of patients with FSGS warrants further investigation
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