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.