Koehler, Sybille, Odenthal, Johanna, Ludwig, Vivian, Jess, David Unnersjo, Hoehne, Martin, Juengst, Christian, Grawe, Ferdi, Helmstaedter, Martin, Janku, Johanna L., Bergmann, Carsten, Hoyer, Peter F., Hagmann, H. Henning, Walz, Gerd, Bloch, Wilhelm, Niessen, Carien, Schermer, Bernhard ORCID: 0000-0002-5194-9000, Wodarz, Andreas, Denholm, Barry, Benzing, Thomas ORCID: 0000-0003-0512-1066, Iden, Sandra and Brinkkoetter, Paul T. (2022). Scaffold polarity proteins Par3A and Par3B share redundant functions while Par3B acts independent of atypical protein kinase C/Par6 in podocytes to maintain the kidney filtration barrier. Kidney Int., 101 (4). S. 733 - 752. NEW YORK: ELSEVIER SCIENCE INC. ISSN 1523-1755

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Abstract

Glomerular diseases are a major cause for chronic kidney disorders. In most cases podocyte injury is causative for disease development. Cytoskeletal rearrangements and morphological changes are hallmark features of podocyte injury and result in dedifferentiation and loss of podocytes. Here, we establish a link between the Par3 polarity complex and actin regulators necessary to establish and maintain podocyte architecture by utilizing mouse and Drosophila models to characterize the functional role of Par3A and Par3B and its fly homologue Bazooka in vivo. Only simultaneous inactivation of both Par3 proteins caused a severe disease phenotype. Rescue experiments in Drosophila nephrocytes revealed atypical protein kinase C (aPKC)-Par6 dependent and independent effects. While Par3A primarily acts via aPKC-Par6, Par3B function was independent of Par6. Actin-associated synaptopodin protein levels were found to be significantly upregulated upon loss of Par3A/B in mouse podocytes. Tropomyosin2, which shares functional similarities with synaptopodin, was also elevated in Bazooka depleted nephrocytes. The simultaneous depletion of Bazooka and Tropomyosin2 resulted in a partial rescue of the Bazooka knockdown phenotype and prevented increased Rho1-GTP, a member of a GTPase protein family regulating the cytoskeleton. The latter contribute to the nephrocyte phenotype observed upon loss of Bazooka. Thus, we demonstrate that Par3 proteins share a high functional redundancy but also have specific functions. Par3A acts in an aPKC-Par6 dependent way and regulates RhoA-GTP levels, while Par3B exploits Par6 independent functions influencing synaptopodin localization. Hence, Par3A and Par3B link elements of polarity signaling and actin regulators to maintain podocyte architecture.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Koehler, SybilleUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Odenthal, JohannaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Ludwig, VivianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Jess, David UnnersjoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoehne, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Juengst, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Grawe, FerdiUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Helmstaedter, MartinUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Janku, Johanna L.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bergmann, CarstenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hoyer, Peter F.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hagmann, H. HenningUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Walz, GerdUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Bloch, WilhelmUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Niessen, CarienUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schermer, BernhardUNSPECIFIEDorcid.org/0000-0002-5194-9000UNSPECIFIED
Wodarz, AndreasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Denholm, BarryUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Benzing, ThomasUNSPECIFIEDorcid.org/0000-0003-0512-1066UNSPECIFIED
Iden, SandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brinkkoetter, Paul T.UNSPECIFIEDUNSPECIFIEDUNSPECIFIED
URN: urn:nbn:de:hbz:38-688927
DOI: 10.1016/j.kint.2021.11.030
Journal or Publication Title: Kidney Int.
Volume: 101
Number: 4
Page Range: S. 733 - 752
Date: 2022
Publisher: ELSEVIER SCIENCE INC
Place of Publication: NEW YORK
ISSN: 1523-1755
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
NEPHROTIC SYNDROME; APKC-LAMBDA/IOTA; CELL POLARITY; DROSOPHILA; SYNAPTOPODIN; REVEALS; GENE; DIFFERENTIATION; ORGANIZATION; EXPRESSIONMultiple languages
Urology & NephrologyMultiple languages
URI: http://kups.ub.uni-koeln.de/id/eprint/68892

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