Journal
JOURNAL OF THE AMERICAN SOCIETY OF NEPHROLOGY
Volume 20, Issue 4, Pages 798-806Publisher
AMER SOC NEPHROLOGY
DOI: 10.1681/ASN.2008080871
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Funding
- Deutsche Forschungsgerneinschaft [HU 1016/2-1, SFB 592]
- DFG [SCHI 587/2-2, SFB 566]
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Atypical protein kinase C (aPKC) is a central component of the evolutionarily conserved Par3-Par6- aPKC complex, one of the fundamental regulators of cell polarity. We recently demonstrated that these proteins interact with Neph-nephrin molecules at the slit diaphragm of the glomerular filtration barrier. Here, we report that podocyte-specific deletion of aPKC lambda/iota in mice results in severe proteinuria, nephrotic syndrome, and death at 4 to 5 wk after birth. Podocyte foot processes of knockout mice developed structural defects, including mislocalization of the slit diaphragm. In the glomerulus, aPKC lambda/iota was primarily expressed in developing glomerular epithelial cells and podocyte foot processes. Interestingly, under physiologic conditions, aPKC lambda/iota translocated from the apical surface to the basolateral side of developing podocytes, and this translocation preceded the development of foot processes and formation of slit diaphragms. Supporting a critical role for aPKC lambda/iota in the maintenance of slit diaphragms and poclocyte foot processes, aPKC lambda/iota associated with the Neph-nephrin slit diaphragm complex and localized to the tips of filopodia and leading edges of cultured podocytes. These results suggest that aPKC signaling is fundamental to glomerular maintenance and development.
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