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J. Biol. Chem., Vol. 278, Issue 21, 19266-19271, May 23, 2003
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Nephrin and Neph1 Co-localize at the Podocyte Foot Process Intercellular Junction and Form cis Hetero-oligomers*
¶
From the
Department of Pediatrics, University of Michigan Medical School, Ann Arbor, Michigan 48109-0676,
¶ Department of Internal Medicine, University of Michigan Medical School, Ann Arbor, Michigan 48109-0676,
|| Institute for Clinical Pathology, University of Vienna, Allgemeines Krankenhaus, Wahringer Guntel 18-20, Vienna, Austria 1090,
** Department of Veterans Affairs, Ann Arbor, Michigan 48105
Glomerular visceral epithelial cells (podocytes) appear to play a central role in maintaining the selective filtration barrier of the renal glomerulus. While the immunoglobulin superfamily member Nephrin was proposed to act as a cell adhesion molecule at the podocyte intercellular junction necessary for maintaining glomerular perm selectivity, the Nephrin ligand has not been identified. The existence of a new subfamily of Nephrin-like molecules including Neph1 was recently described. Genetic deletion of Nephrin or Neph1 resulted in similar phenotypes of podocyte foot process effacement and proteinuria. The subcellular localization of Neph1 and the possibility that Nephrin and Neph1 interact was investigated. Polyclonal antiserum for Neph1 was raised and characterized. Neph1 migrated as a 90-kDa protein on SDS-PAGE under reducing conditions. Neph1 was identified in a glomerular and podocyte-specific distribution in adult rat kidney. Like Nephrin and Podocin, Neph1 was enriched in Triton X-100 detergent-resistant membrane fractions. Consistent with this observation, immunogold electron microscopy demonstrated that Neph1 localized exclusively to lateral margins of podocyte foot processes at the insertion of the slit diaphragm. Neph1 and Nephrin participate in a direct cis-interaction involving their cytoplasmic domains. In addition, interactions between the extracellular domain of Nephrin and itself and between the extracellular domain of Nephrin and that of Neph1 were detected. Neph1 did not interact via a homophilic interaction. These observations suggest that Nephrin and Neph1 form a hetero-oligomeric receptor complex in the plane of the membrane that might interact across the foot process intercellular junction through interactions between Nephrin with itself and Neph1.
Received for publication, February 5, 2003 , and in revised form, March 10, 2003.
To whom correspondence should be addressed: University of Michigan Medical School, 1560 MSRB II, Ann Arbor, MI 48109-0676. Tel.: 734-764-3157; Fax: 734-763-0982; E-mail: lholzman{at}umich.edu.
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