Ligation of alpha-dystroglycan on podocytes induces intracellular signaling: a new mechanism for podocyte effacement?
BACKGROUND
Alpha-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 beta-dystroglycan. At the basolateral side alpha-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 alpha-dystroglycan with specific antibodies or natural ligands induces intracellular signaling, and whether there is an effect on podocyte architecture.


RESULTS
Conditionally immortalized podocytes were exposed in vitro to antibodies to alpha-dystroglycan, and to fibronectin, biglycan, laminin and agrin. Intracellular calcium fluxes, phosphorylation of beta-dystroglycan and podocyte architecture were studied. Antibodies to alpha-dystroglycan could specifically induce calcium signaling. Fibronectin also induced calcium signaling, and led to dephosphorylation of pY892 in beta-dystroglycan. Ligation of alpha-dystroglycan resulted in an altered actin architecture, a decreased number of podocyte pedicles and a more flattened appearance of the podocyte.


CONCLUSIONS
We conclude that ligation of alpha-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.
Vogtländer
Nils P J
NP
Nephrology Research Laboratory, Nijmegen Centre for Molecular Life Sciences, Nijmegen, The Netherlands.
Visch
Henk Jan
HJ
Bakker
Marinka A H
MA
Berden
Jo H M
JH
van der Vlag
Johan
J
D000199:Actins / Q000378:metabolism; D000818:Animals; D002118:Calcium / Q000378:metabolism; D020013:Calcium Signaling; D003599:Cytoskeleton / Q000378:metabolism; D049030:Dystroglycans / Q000378:metabolism / Q000502:physiology*; D005353:Fibronectins / Q000378:metabolism; D006023:Glycoproteins / Q000378:metabolism; D007678:Kidney Glomerulus / Q000378:metabolism; D008024:Ligands; D051379:Mice; D008954:Models, Biological; D050199:Podocytes / Q000378:metabolism*; D015398:Signal Transduction
D000199:Actins; D005353:Fibronectins; D006023:Glycoproteins; D008024:Ligands; D049030:Dystroglycans; D002118:Calcium