Loss of podocyte aPKClambda/iota causes polarity defects and nephrotic syndrome

TY - JOUR

T1 - Loss of podocyte aPKClambda/iota causes polarity defects and nephrotic syndrome

AU - Huber, Tobias B

AU - Hartleben, Björn

AU - Winkelmann, Kirstin

AU - Schneider, Lisa

AU - Becker, Jan U

AU - Leitges, Michael

AU - Walz, Gerd

AU - Haller, Hermann

AU - Schiffer, Mario

PY - 2009/4

Y1 - 2009/4

N2 - 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 aPKClambda/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, aPKClambda/iota was primarily expressed in developing glomerular epithelial cells and podocyte foot processes. Interestingly, under physiologic conditions, aPKClambda/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 aPKClambda/iota in the maintenance of slit diaphragms and podocyte foot processes, aPKClambda/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.

AB - 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 aPKClambda/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, aPKClambda/iota was primarily expressed in developing glomerular epithelial cells and podocyte foot processes. Interestingly, under physiologic conditions, aPKClambda/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 aPKClambda/iota in the maintenance of slit diaphragms and podocyte foot processes, aPKClambda/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.

KW - Animals

KW - Cell Polarity

KW - Death

KW - Gene Deletion

KW - Isoenzymes

KW - Kidney Glomerulus

KW - Mice

KW - Mice, Knockout

KW - Nephrotic Syndrome

KW - Podocytes

KW - Protein Kinase C

KW - Proteinuria

KW - Journal Article

KW - Research Support, Non-U.S. Gov't

U2 - 10.1681/ASN.2008080871

DO - 10.1681/ASN.2008080871

M3 - SCORING: Journal article

C2 - 19279126

VL - 20

SP - 798

EP - 806

JO - J AM SOC NEPHROL

JF - J AM SOC NEPHROL

SN - 1046-6673

IS - 4

ER -