Podocyte Sphingolipid Signaling in Nephrotic Syndrome

Abstract

Podocytes play a vital role in the pathogenesis of nephrotic syndrome (NS), which is clinically characterized by heavy proteinuria, hypoalbuminemia, hyperlipidemia, and peripheral edema. The pathogenesis of NS has evolved through several hypotheses ranging from immune dysregulation theory and increased glomerular permeability theory to the current concept of podocytopathy. Podocytopathy is characterized by dysfunction or depletion of podocytes, which may be caused by unknown permeability factor, genetic disorders, drugs, infections, systemic disorders, and hyperfiltration. Over the last two decades, numerous studies have been done to explore the molecular mechanisms of podocyte injuries or NS and to develop the novel therapeutic strategies targeting podocytopathy for treatment of NS. Recent studies have shown that normal sphingolipid metabolism is essential for structural and functional integrity of podocytes. As a basic component of the plasma membrane, sphingolipids not only support the assembly of signaling molecules and interaction of receptors and effectors, but also mediate various cellular activities, such as apoptosis, proliferation, stress responses, necrosis, inflammation, autophagy, senescence, and differentiation. This review briefly summarizes current evidence demonstrating the regulation of sphingolipid metabolism in podocytes and the canonical or noncanonical roles of podocyte sphingolipid signaling in the pathogenesis of NS and associated therapeutic strategies.

Keywords: Sphingolipid; Acid ceramidase; Sphingomyelin-like phosphodiesterase 3b; Podocyte; Nephrotic syndrome.

Fig. 1.

Sphingolipid metabolic pathways. De novo synthesis of ceramide consists of decarboxylation of a serine residue and condensation with a fatty acyl-CoA. Hydrolysis of SM by various SMases can also produce ceramide. The subsequent reactions catalyzed by CK, GCS, and GalCS lead to the production of other sphingolipids from ceramide. Many of these biochemical reactions are bidirectional. C1PP, ceramide-1-phosphate phosphatase; CDase, ceramidases; CK, ceramide kinase; CerS, ceramide synthase; DAG, diacylglycerol; DES, dihydroceramide desaturases; GalCS, galactosylceramide synthase; GCase, glucocylceramidase; GCS, glucosylceramide synthase; PC, phosphatidylcholine; S1P, sphingosine-1-phosphate; S1PP, S1P phosphatase; SK, sphingosine kinase; SMase, sphingomyelinase; SMS, sphingomyelinase synthase; SPL, S1P lyase; SPT, serine palmitoyl transferase.

Fig. 2.

Regulation of slit diaphragm and actin cytoskeleton by sphingolipids and modulating enzymes in podocytes. Normal level of GD3 is essential for the maintenance of slit diaphragm in podocytes. Lack of GD3 leads to enhanced phosphorylation of nephrin, leading to increased translocation of nephrin to cytosol. GM3, together with Flt1 and SRB1, plays an important role in the regulation of actin cytoskeleton in podocytes. Overproduction of ceramide by NSM enhances the phosphorylation of Ezrin by PP2A, leading to actin cytoskeleton remodeling in podocytes. The expression of SMPDL3b on plasma membrane is vital for the maintenance of actin cytoskeleton in podocytes. Elevated suPAR is associated with reduction of SMPDL3b on plasma membrane, leading to actin cytoskeleton remodeling in podocytes. GD3, O-acetylated disialosyllactosylceramide; GM3, ganglioside GM3; Flt1, vascular endothelial growth factor receptor 1; SRB1, scavenger receptor class B type 1; NSM, neutral sphingomyelinase; PP2A, protein phosphatase 2A; suPAR, soluble urokinase plasminogen activator receptor.

Fig. 3.

Regulation of lysosome function by sphingolipids and modulating enzymes in podocytes. Lysosome trafficking and fusion to autophagosome and MVB are dependent on the TRPML1 channel-mediated Ca²⁺ release in podocytes. Lysosomal ASM converts SM into CER and AC converts CER to Sph. These sphingolipids, SM, Cer, and Sph had different effects on TRPML1 channel activity in podocytes, with inhibition by SM, no effect from Cer, but enhancement by Sph. SM, sphingomyelin; Cer; ceramide; Sph, sphingosine.