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Podocyte Flattening and Disorder of Glomerular Basement Membrane Are Associated with Splitting of Dystroglycan-Matrix Interaction

Kenichiro Kojima^*,, Agnes Davidovits, Helga Poczewski, Brigitte Langer, Shunya Uchida^*, Katalyn Nagy-Bojarski, Anny Hovorka, Roland Sedivy and Dontscho Kerjaschki

Institute of Clinical Pathology, Medical University of Vienna-Allgemeines Krankenhaus, Vienna, Austria; and *Division of Nephrology, Department of Medicine, Teikyo University School of Medicine, Tokyo, Japan.

Correspondence to Dr. Dontscho Kerjaschki, Institute of Pathology, Medical University of Vienna-Allgemeines Krankenhaus, Währinger Gürtel 18-20, A-1090 Vienna, Austria. Phone: 43-1-40400-5176; Fax: 43-1-40400-5193; E-mail: dontscho.kerjaschki{at}meduniwien.ac.at

ABSTRACT. The transmembrane component of the dystroglycan complex, a heterodimer of - and -dystroglycan, was recently localized at the basal cell membrane domain of podocytes, and it was speculated that it serves as a device of the podocyte for maintaining the complex podocyte foot process architecture, and for regulating the exact position of its ligands, the matrix proteins laminin and agrin, in the glomerular basement membrane (GBM). The redistribution of dystroglycan in two experimental rat models of foot process flattening and proteinuria—i.e., podocyte damage induced by polycationic protamine sulfate perfusion, and reactive oxygen species (ROS)-associated puromycin aminonucleoside nephrosis—was examined. In both experimental diseases, aggregation and reduced density of -dystroglycan by endocytosis by podocytes was observed. In in vitro solid-phase binding assays, protamine and ROS competed with the binding of -dystroglycan with purified laminin and a recombinant C-terminal fragment of agrin that contains the dystroglycan-binding domain. These changes were associated with disorder of the fibrillar components of the lamina rara externa of the GBM, as confirmed quantitatively by fractal analysis. These results indicate that both polycation and ROS induce similar changes in the distribution of podocyte -dystroglycan that involve competitive disruption of -dystroglycan/matrix protein complexes, endocytosis of the liberated receptor by podocytes, and disorganization of the matrix protein arrangement in the lamina rara externa. This links functional damage of the dystroglycan complex with structural changes in the GBM.

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