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(American Journal of Pathology. 2000;157:1905-1916.)
© 2000 American Society for Investigative Pathology

Regular Articles

Role of Nephrin in Cell Junction Formation in Human Nephrogenesis

Vesa Ruotsalainen^*, Jaakko Patrakka, Päivi Tissari^*, Paula Reponen, Michael Hess^§, Marjo Kestilä^*, Christer Holmberg, Riitta Salonen, Markku Heikinheimo^||, Jorma Wartiovaara^§, Karl Tryggvason^** and Hannu Jalanko

From the Biocenter and Department of Biochemistry,^*
University of Oulu, Oulu, Finland; the Hospital for Children and Adolescents,
University of Helsinki, Pediatric Nephrology and Transplantation, Helsinki, Finland; the Department of Bacteriology and Immunology,
Haartman Institute, University of Helsinki, Helsinki, Finland; the Electron Microscopy Unit,^§
Institute of Biotechnology, University of Helsinki, Helsinki, Finland; the Department of Obstetrics and Gynecology, University of Helsinki, Helsinki, Finland; the Department of Pediatrics,^||
Washington University, St. Louis, Missouri; and the Division of Matrix Biology,^**
Department of Medical Biochemistry and Biophysics, Karolinska Institute, Stockholm, Sweden

Nephrin is a cell adhesion protein located at the slit diaphragm area of glomerular podocytes. Mutations in nephrin-coding gene (NPHS1) cause congenital nephrotic syndrome (NPHS1). We studied the developmental expression of nephrin, ZO-1 and P-cadherin in normal fetal kidneys and in NPHS1 kidneys. We used in situ hybridization and immunohistochemistry at light and electron microscopic levels. Nephrin and zonula occludens-1 (ZO-1) were first expressed in late S-shaped bodies. During capillary loop stage, nephrin and ZO-1 localized at the basal margin and in the cell-cell adhesion sites between developing podocytes, especially in junctions with ladder-like structures. In mature glomeruli, nephrin and ZO-1 concentrated at the slit diaphragm area. P-cadherin was first detected in ureteric buds, tubules, and vesicle stage glomeruli. Later, P-cadherin was seen at the basal margin of developing podocytes. Fetal NPHS1 kidneys with Fin-major/Fin-major genotype did not express nephrin, whereas the expression of ZO-1 and P-cadherin was comparable to that of control kidneys. Although early junctional complexes proved structurally normal, junctions with ladder-like structures and slit diaphragms were completely missing. The results indicate that nephrin is dispensable for early development of podocyte junctional complexes. However, nephrin appears to be essential for formation of junctions with ladder-like structures and slit diaphragms.

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