Abstract
Backgroundα-Dystroglycan is a negatively charged glycoprotein that covers the apical and basolateral membrane of the podocyte. Its transmembrane binding to the cytoskeleton is regulated via tyrosine phosphorylation (pY892) of β-dystroglycan. At the basolateral side α-dystroglycan binds the glomerular basement membrane. At the apical membrane, it plays a role in the maintenance of the filtration slit. In this study, we evaluated whether ligation of α-dystroglycan with specific antibodies or natural ligands induces intracellular signaling, and whether there is an effect on podocyte architecture.Methodology/Principal FindingsConditionally immortalized podocytes were exposed in vitro to antibodies to α-dystroglycan, and to fibronectin, biglycan, laminin and agrin. Intracellular calcium fluxes, phosphorylation of β-dystroglycan and podocyte architecture were studied. Antibodies to α-dystroglycan could specifically induce calcium signaling. Fibronectin also induced calcium signaling, and led to dephosphorylation of pY892 in β-dystroglycan. Ligation of α-dystroglycan resulted in an altered actin architecture, a decreased number of podocyte pedicles and a more flattened appearance of the podocyte.Conclusions/SignificanceWe conclude that ligation of α-dystroglycan on podocytes induces intracellular calcium signaling, which leads to an altered cytoskeleton architecture akin to the situation of foot process effacement. In particular the ability of fibronectin to induce intracellular signaling events is of interest, since the expression and excretion of this protein is upregulated in several proteinuric diseases. Therefore, fibronectin-induced signaling via dystroglycan may be a novel mechanism for foot process effacement in proteinuric diseases.
Highlights
Podocytes are highly specialized glomerular visceral epithelial cells that cover the outside of the glomerular basement membrane [1]
Dystroglycan provides a link between the extracellular matrix like the glomerular basement membrane to the actin cytoskeleton of the podocyte. a- Dystroglycan binds to laminin G modules that are present in laminin and agrin, whereas b-dystroglycan is connected to the actin cytoskeleton via dystrophin or its ubiquitous homologue utrophin in the kidney [6,8,9]. a-Dystroglycan undergoes massive O-mannosyl glycosilation with terminal sialic acids, which serve by virtue of their negative charge as an anti-adhesion layer on the apical podocyte membrane, analogous to podocalyxin, a sialic acid-rich glycoprotein that covers the apical cell membrane of the podocyte [7]
Monoclonal antibody IIH6 inhibits the binding of mouse podocytes to laminin EHS and agrin, indicating an important role for adystroglycan for the binding of podocytes to laminin G modules containing proteins such as laminin and agrin in the glomerular basement membrane
Summary
Podocytes are highly specialized glomerular visceral epithelial cells that cover the outside of the glomerular basement membrane [1]. Dystroglycan provides a link between the extracellular matrix like the glomerular basement membrane to the actin cytoskeleton of the podocyte. A- Dystroglycan binds to laminin G modules that are present in laminin and agrin, whereas b-dystroglycan is connected to the actin cytoskeleton via dystrophin or its ubiquitous homologue utrophin in the kidney [6,8,9]. A-Dystroglycan undergoes massive O-mannosyl glycosilation with terminal sialic acids, which serve by virtue of their negative charge as an anti-adhesion layer on the apical podocyte membrane, analogous to podocalyxin, a sialic acid-rich glycoprotein that covers the apical cell membrane of the podocyte [7]. We have shown previously that deglycosilation of adystroglycan by reactive oxygen species results in a loss of binding to agrin and laminin [10]
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