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Podocytes Are Firmly Attached to Glomerular Basement Membrane in Kidneys with Heavy Proteinuria

Anne-Tiina Lahdenkari^*, Kari Lounatmaa, Jaakko Patrakka^*,, Christer Holmberg^*, Jorma Wartiovaara, Marjo Kestilä^||, Olli Koskimies^* and Hannu Jalanko^*

*Hospital for Children and Adolescents and Biomedicum Helsinki, University of Helsinki, Helsinki, Finland; Helsinki University of Technology, Laboratory of Electronics Production Technology, Espoo, Finland; Division of Matrix Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institut, Stockholm, Sweden; Electron Microscopy Unit, Institute of Biotechnology, University of Helsinki, Helsinki, Finland; and ^||Department of Molecular Medicine, National Public Health Institute, Helsinki, Finland

Correspondence to Dr. Hannu Jalanko, Hospital for Children and Adolescents, University of Helsinki, 00290 Helsinki, Finland. Phone: +358-9-47173708; Fax: +358-9-47173700; E-mail: hannu.jalanko{at}hus.fi

Glomerular epithelial cells (podocytes) play an important role in the pathogenesis of proteinuria. Podocyte foot process effacement is characteristic for proteinuric kidneys, and genetic defects in podocyte slit diaphragm proteins may cause nephrotic syndrome. In this work, a systematic electron microscopic analysis was performed of the structural changes of podocytes in two important nephrotic kidney diseases, congenital nephrotic syndrome of the Finnish type and minimal-change nephrotic syndrome (MCNS). The results showed that (1) podocyte foot process effacement was present not only in proteinuric glomeruli but also in nonproteinuric MCNS kidneys; (2) podocytes in proteinuric glomeruli did not show detachment from the basement membrane or cell membrane ruptures; (3) the number of pinocytic membrane invaginations in the basal and apical parts of the podocytes was comparable in proteinuric and control kidneys; (4) in proteinuric kidneys, the podocyte slit pore density was decreased by 69 to 80% and up to half of the slits were so "tight" that no visible space between foot processes was seen; thus, the filtration surface area between podocytes was dramatically reduced; and (5) in the narrow MCNS slit pores, nephrin was located in the apical part of the podocyte foot process, indicating vertical transfer of the slit diaphragm complex in proteinuria. In conclusion, these results suggest that protein leakage in the two nephrotic syndromes studied occurs through defective podocyte slits, and the other structural alterations commonly seen in electron microscopy are secondary to, not a prerequisite for, the development of proteinuria.

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