Podocytes as a Direct Target of Drugs Used in Idiopathic Nephrotic Syndrome

Fig. 13.1

Signalling pathways targeted by different drugs in podocytes. The glomerular capillary wall comprises of three components: glomerular endothelial cells, GBM (glomerular basement membrane) and podocytes. With its unique properties and importance for maintaining the function of the glomerular filtration barrier, the podocyte has been suggested as a promising target for future specific therapies for proteinuric disease. Drugs that are currently used in the treatment of idiopathic nephrotic syndrome have been shown to exert direct effects on podocytes via different mechanisms: (1) Induction of CD80 results in disruption of SD complex. Blocking of this pathway may be involved in the protective effects of glucocorticoids (GCs), abatacept and levamisole on podocytes. By binding to CD80, abatacept reduces proteinuria likely by stabilising β1-integrin activation in podocytes. GCs act through binding to GR (glucocorticoid receptor). This receptor is also suggested to be involved in the actions of levamisole on podocytes. (2) Phosphorylation of Akt is decreased in podocyte injury. GCs and levamisole can restore Akt phosphorylation to promote podocyte survival. (3) ROS is another factor causing podocyte injury and apoptosis. GCs prevent podocyte apoptosis by reducing ROS, decreasing p53 expression and increasing Bcl-xL expression. Expression and translocation of AIF (apoptosis-inducing factor) can be blocked by both GCs and levamisole. (4) GTPase RhoA is a key regulator of actin cytoskeleton. This pathway has been shown to be targeted by GCs and by mTOR inhibitor everolimus and to be involved in their effects of stabilising podocyte actin cytoskeleton. (5) Expression and phosphorylation of nephrin is critical for maintaining the integrity and function of SD complex. GCs can increase nephrin expression. They also increase phosphorylation of nephrin via regulation of Nck and Fyn pathway. (6) Synaptopodin is an actin-associated podocyte protein and can be dephosphorylated by calcineurin activation resulting in cleavage and degradation mediated by Cat L (cathepsin L), which can be blocked by calcineurin inhibitor cyclosporin. When calcineurin is blocked, phosphorylated synaptopodin binds to 14-3-3 protein and is subsequently protected from degradation. Calcineurin activation could be caused by TRPC6 (transient potential cation channel 6)-mediated calcium influx. (7) Changes in distribution or expression of tight junction protein ZO-1 (zonula occludens-1) in podocytes are associated with proteinuria. Cyclosporin shows a stabilising effect on ZO-1 expression which is thought to be likely an indirect effect from stabilisation of synaptopodin. (8) Rituximab has been shown to be able to preserve the podocyte actin cytoskeleton and prevent apoptosis by binding and stabilising SMPDL-3b (sphingomyelin phosphodiesterase acid-like 3b) protein in podocytes. (9) Mizoribine promotes podocyte survival by inhibiting activation of ILK (integrin-linked kinase) and phosphorylation of GSK3β (glycogen synthase kinase-3β). The signalling pathways or molecules shown above may represent targets for future podocyte-specific therapies

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