title: An essential role of the universal polarity protein, aPKClambda, on the maintenance of podocyte slit diaphragms.
abstract: Glomerular visceral epithelial cells (podocytes) contain interdigitated processes that form specialized intercellular junctions, termed slit diaphragms, which provide a selective filtration barrier in the renal glomerulus. Analyses of disease-causing mutations in familial nephrotic syndromes and targeted mutagenesis in mice have revealed critical roles of several proteins in the assembly of slit diaphragms. The nephrin-podocin complex is the main constituent of slit diaphragms. However, the molecular mechanisms regulating these proteins to maintain the slit diaphragms are still largely unknown. Here, we demonstrate that the PAR3-atypical protein kinase C (aPKC)-PAR6beta cell polarity proteins co-localize to the slit diaphragms with nephrin. Furthermore, selective depletion of aPKClambda in mouse podocytes results in the disassembly of slit diaphragms, a disturbance in apico-basal cell polarity, and focal segmental glomerulosclerosis (FSGS). The aPKC-PAR3 complex associates with the nephrin-podocin complex in podocytes through direct interaction between PAR3 and nephrin, and the kinase activity of aPKC is required for the appropriate distribution of nephrin and podocin in podocytes. These observations not only establish a critical function of the polarity proteins in the maintenance of slit diaphragms, but also imply their potential involvement in renal failure in FSGS.
authors.affiliation: Department of Molecular Biology, Yokohama City University Graduate School of Medical Science, Yokohama, Kanagawa, Japan.
authors.forename: Tomonori
authors.initials: T
authors.lastname: Hirose
authors.forename: Daisuke
authors.initials: D
authors.lastname: Satoh
authors.forename: Hidetake
authors.initials: H
authors.lastname: Kurihara
authors.forename: Chiho
authors.initials: C
authors.lastname: Kusaka
authors.forename: Hiroko
authors.initials: H
authors.lastname: Hirose
authors.forename: Kazunori
authors.initials: K
authors.lastname: Akimoto
authors.forename: Taiji
authors.initials: T
authors.lastname: Matsusaka
authors.forename: Iekuni
authors.initials: I
authors.lastname: Ichikawa
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Noda
authors.forename: Shigeo
authors.initials: S
authors.lastname: Ohno
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism*; D000818:Animals; D015815:Cell Adhesion Molecules / Q000378:metabolism*; D018797:Cell Cycle Proteins; D016764:Cell Polarity; D005923:Glomerulosclerosis, Focal Segmental; D007365:Intercellular Junctions; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D007527:Isoenzymes / Q000378:metabolism / Q000502:physiology*; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D046912:Multiprotein Complexes; D050199:Podocytes / Q000648:ultrastructure*; D011493:Protein Kinase C / Q000378:metabolism / Q000502:physiology*; D000099293:Protein Kinase C-lambda
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D015815:Cell Adhesion Molecules; D018797:Cell Cycle Proteins; D047908:Intracellular Signaling Peptides and Proteins; D007527:Isoenzymes; D008565:Membrane Proteins; D046912:Multiprotein Complexes; D011493:Protein Kinase C; D000099293:Protein Kinase C-lambda; C407223:NPHS2 protein; C518597:Par6 protein, mouse; C115084:Pard3 protein, mouse; C113267:nephrin