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

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 as ne...

Full description

Saved in:
Bibliographic Details
Published in:Journal of biochemistry (Tokyo) 2014-08, Vol.156 (2), p.115-128
Main Authors: Satoh, Daisuke, Hirose, Tomonori, Harita, Yutaka, Daimon, Chikara, Harada, Tomonori, Kurihara, Hidetake, Yamashita, Akio, Ohno, Shigeo
Format: Article
Language:English
Subjects:
Animals
Cell Membrane - metabolism
Endocytosis
Exocytosis
HCT116 Cells
Humans
Male
Membrane Proteins - metabolism
Mice, Knockout
Podocytes - metabolism
Protein Kinase C - physiology
Protein Transport
Rats, Wistar
Regular Papers
Citations: Items that this one cites
Items that cite this one
Online Access:Get full text
Tags: Add Tag
No Tags, Be the first to tag this record!
Description
Summary: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 as nephrin, 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.
ISSN:0021-924X
1756-2651
DOI:10.1093/jb/mvu022