Therapeutic targets in focal and segmental glomerulosclerosis - PubMed (original) (raw)

Review

Therapeutic targets in focal and segmental glomerulosclerosis

Peter J Lavin et al. Curr Opin Nephrol Hypertens. 2008 Jul.

Abstract

Purpose of review: Focal and segmental glomerulosclerosis occurs due to a defect in the glomerular filtration barrier. This review highlights contributions from the past year that have enhanced our understanding of the pathophysiology of focal and segmental glomerulosclerosis with emphasis on discoveries which may lead to the identification of therapeutic targets.

Recent findings: Slit diaphragm proteins have become increasingly important in signal transduction and in mediating downstream events. Actin polymerization occurs after the podocin-nephrin-Neph-1 complex is phosphorylated by Src kinase and Fyn. Recent studies of angiotensin receptor antagonists, corticosteroids and erythropoietin unravel new mechanisms that ameliorate proteinuria by targeting the cell cycle within the podocyte. The discovery that an N-acetylmannosamine kinase (MNK) mutant mouse has glomerulopathy is suggestive that human sialylation pathways may represent therapeutic targets. Proteinuria before podocyte effacement demonstrated in laminin-beta2 null mice highlights the importance of the glomerular basement membrane. Interferon-beta reduced proteinuria in three models of kidney injury, showing greatest effect on glomerular endothelial cells in vitro.

Summary: Basic research has illuminated mechanisms by which classic therapies have antiproteinuric effects directly on the podocyte. As knowledge expands with improved molecular techniques, understanding signaling pathways in health and proteinuric states should lead to potential therapeutic targets in focal and segmental glomerulosclerosis.

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Figures

Figure 1

Figure 1

(1) Phosphorylation of the nephrin protein by Fyn kinase via the adapter protein Nck that induces actin polymerization [10]. (2) Neph1 phosphorylation by Fyn kinase and recruitment of Grb2 induces actin polymerization [12•]. (3) Specific blockade of the TRPC6 channel may be a useful therapy in FSGS [13]. (4) Identification of mutations in PLCε1 may identify a subset of patients who are amenable to standard therapy [18]. (5) Modulation of sialylation pathways may represent therapeutic targets with the discovery that an MNK null mouse has a glomerular phenotype [17••]. (6) Lysosomal cathepsin (CATL), present in podocyte cytoplasm in acquired proteinuric kidney disease, cleaves dynamin leading to filopodia formation, podocyte effacement and proteinuria [16•]. Modulation of CATL or dynamin may be a useful in therapy of FSGS. (7) Synaptopodin binds insulin receptor substrate p53 (IRSP3) preventing its binding with the small GTPases (Rac1, Cdc42 and Mena) thereby preventing filopodia formation and proteinuria [15•]. (8) Induction of urokinase plasminogen activator receptor (uPAR) causes proteinuria through lipid dependent activation of αvβ3 integrin. Inhibition of αvβ3 integrin resulted in reduced podocyte motility and proteinuria [14•]. ACTN4, α-actinin-4; CAS, p130Cas, an adaptor protein (Crk-associated substrate); CD2AP, CD2-associated protein; FAK, focal adhesion kinase; Fat1, cadherin Fat1; Grb2, growth factor receptor-bound protein 2; Nck, Nck adapter protein; TPV, talin, paxillin, and vinculin complex; ZO-1, zonula occluden-1. Adapted with permission [19,20] and updated with information from the legend and text.

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