Home » Key Scientific Articles » aPKCλ maintains the integrity of the glomerular slit diaphragm through trafficking of nephrin to the cell surface.

aPKCλ maintains the integrity of the glomerular slit diaphragm through trafficking of nephrin to the cell surface.

Satoh D1, Hirose T1, Harita Y2, Daimon C1, Harada T1, Kurihara H1, Yamashita A1, Ohno S3.

J Biochem. 2014 Aug;156(2):115-28.1Department of Molecular Biology, Graduate School of Medical Science, Yokohama City University, Yokohama;

2Department of Pediatrics, Graduate School of Medicine, The University of Tokyo, Tokyo;

3Department of Pediatrics, Yokohama City University, Yokohama;

4Department of Anatomy, Juntendo University, School of Medicine, Bunkyo, Tokyo; and

5Advanced Medical Research Center, Yokohama City University, Yokohama, Kanagawa, Japan.

 

Abstract

 

The slit diaphragm (SD), the specialized intercellular junction between renal glomerular epithelial cells (podocytes), provides a selective-filtration barrier in renal glomeruli. Dysfunction of the SD results in glomerular diseases that are characterized by disappearance of SD components, such asnephrin, from the cell surface. Although the importance of endocytosis and degradation of SD components for the maintenance of SD integrity has been suggested, the dynamic nature of the turnover of intact cell-surface SD components remained unclear. Using isolated rat glomeruli we show that the turnover rates of cell-surface SD components are relatively high; they almost completely disappear from the cell surface within minutes. The exocytosis, but not endocytosis, of heterologously expressed nephrin requires the kinase activity of the cell polarity regulator atypical protein kinase C (aPKC). Consistently, we demonstrate that podocyte-specific deletion of aPKCλ resulted in a decrease of cell-surface localization of SD components, causing massive proteinuria. In conclusion, the regulation of SD turnover by aPKC is crucial for the maintenance of SD integrity and defects in aPKC signalling can lead to proteinuria. These findings not only reveal the pivotal importance of the dynamic turnover of cell-surface SD components but also suggest a novel pathophysiological basis in glomerular disease.

© The Authors 2014. Published by Oxford University Press on behalf of the Japanese Biochemical Society.

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