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Loss of Podocyte aPKC/ Causes Polarity Defects and Nephrotic Syndrome

Tobias B. Huber^*, Björn Hartleben^*, Kirstin Winkelmann, Lisa Schneider^*, Jan U. Becker, Michael Leitges, Gerd Walz^*, Hermann Haller and Mario Schiffer

^* Renal Division, University Hospital Freiburg, Freiburg, Germany; Division of Nephrology, Department of Medicine, and Department of Pathology, Hannover Medical School, Hannover, Germany; and Biotechnology Centre of Oslo, University of Oslo, Oslo, Norway

Correspondence: Dr. Tobias B. Huber, Renal Division, University Hospital Freiburg, Breisacher Strasse 66, D-79106 Freiburg, Germany. Phone: +49-761-270-3559; Fax: +49-761-270-3270; E-mail: tobias.huber{at}uniklinik-freiburg.de

Received for publication August 19, 2008. Accepted for publication November 11, 2008.

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/ 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/ was primarily expressed in developing glomerular epithelial cells and podocyte foot processes. Interestingly, under physiologic conditions, aPKC/ 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/ in the maintenance of slit diaphragms and podocyte foot processes, aPKC/ 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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Copyright © 2009 by the American Society of Nephrology. Online ISSN: 1533-3450 Print ISSN: 1046-6673