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Cell death & disease
07 21, 2016;7 e2302.

Tankyrase inhibition aggravates kidney injury in the absence of CD2AP.

S Kuusela, H Wang, A A Wasik, H Suleiman, S Lehtonen
Author Information
  1. S Kuusela: Department of Pathology, University of Helsinki, Helsinki, Finland.
  2. H Wang: Department of Pathology, University of Helsinki, Helsinki, Finland.
  3. A A Wasik: Department of Pathology, University of Helsinki, Helsinki, Finland.
  4. H Suleiman: HHMI/Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, USA.
  5. S Lehtonen: Department of Pathology, University of Helsinki, Helsinki, Finland. ORCID
PMID: 27441654 DOI: 10.1038/cddis.2016.217

Abstract

Inappropriate activation of the Wnt/β-catenin pathway has been indicated in podocyte dysfunction and injury, and shown to contribute to the development and progression of nephropathy. Tankyrases, multifunctional poly(ADP-ribose) polymerase (PARP) superfamily members with features of both signaling and cytoskeletal proteins, antagonize Wnt/β-catenin signaling. We found that tankyrases interact with CD2-associated protein (CD2AP), a protein essential for kidney ultrafiltration as CD2AP-knockout (CD2AP-/-) mice die of kidney failure at the age of 6-7 weeks. We further observed that tankyrase-mediated total poly-(ADP-ribosyl)ation (PARylation), a post-translational modification implicated in kidney injury, was increased in mouse kidneys and cultured podocytes in the absence of CD2AP. The data revealed increased activity of β-catenin, and upregulation of lymphoid enhancer factor 1 (LEF1) (mediator of Wnt/β-catenin pathway) and fibronectin (downstream target of Wnt/β-catenin) in CD2AP-/- podocytes. Total PARylation and active β-catenin were reduced in CD2AP-/- podocytes by tankyrase inhibitor XAV939 treatment. However, instead of ameliorating podocyte injury, XAV939 further upregulated LEF1, failed to downregulate fibronectin and induced plasminogen activator inhibitor-1 (PAI-1) that associates with podocyte injury. In zebrafish, administration of XAV939 to CD2AP-depleted larvae aggravated kidney injury and increased mortality. Collectively, the data reveal sustained activation of the Wnt/β-catenin pathway in CD2AP-/- podocytes, contributing to podocyte injury. However, we observed that inhibition of the PARylation activity of tankyrases in the absence of CD2AP was deleterious to kidney function. This indicates that balance of the PARylation activity of tankyrases, maintained by CD2AP, is essential for normal kidney function. Furthermore, the data reveal that careful contemplation is required when targeting Wnt/β-catenin pathway to treat proteinuric kidney diseases associated with impaired CD2AP.

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Grants

  1. 242820/European Research Council

MeSH Term

Adaptor Proteins, Signal Transducing
Animals
Cell Line, Transformed
Cytoskeletal Proteins
Embryo, Nonmammalian
Fibronectins
Genes, Lethal
HEK293 Cells
Heterocyclic Compounds, 3-Ring
Humans
Lymphoid Enhancer-Binding Factor 1
Male
Mice
Mice, Knockout
Podocytes
Poly Adenosine Diphosphate Ribose
Protein Processing, Post-Translational
Rats
Rats, Sprague-Dawley
Renal Insufficiency
Serpin E2
Signal Transduction
Tankyrases
Zebrafish
beta Catenin

Chemicals

Adaptor Proteins, Signal Transducing
CD2-associated protein
CTNNB1 protein, mouse
Cytoskeletal Proteins
Fibronectins
Heterocyclic Compounds, 3-Ring
Lef1 protein, mouse
Lymphoid Enhancer-Binding Factor 1
Serpin E2
Serpine2 protein, mouse
XAV939
beta Catenin
Poly Adenosine Diphosphate Ribose
Tankyrases
Tnks protein, mouse
tankyrase-2, mouse
Journal Article Research Support, Non-U.S. Gov't
Article has an altmetric score of 7

Word Cloud

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