Tankyrase inhibition aggravates kidney injury in the absence of CD2AP

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http://hdl.handle.net/10138/167084

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Kuusela , S , Wang , H , Wasik , A , Suleiman , H & Lehtonen , S 2016 , ' Tankyrase inhibition aggravates kidney injury in the absence of CD2AP ' , Cell Death and Disease , vol. 7 . https://doi.org/10.1038/cddis.2016.217

Title: Tankyrase inhibition aggravates kidney injury in the absence of CD2AP
Author: Kuusela, S.; Wang, Hong; Wasik, Anita; Suleiman, H.; Lehtonen, S.
Contributor: University of Helsinki, Sanna Lehtonen research group
University of Helsinki, Medicum
University of Helsinki, Department of Pathology
University of Helsinki, Medicum
Date: 2016-07
Language: eng
Number of pages: 13
Belongs to series: Cell Death and Disease
ISSN: 2041-4889
URI: http://hdl.handle.net/10138/167084
Abstract: Inappropriate activation of the Wnt/beta-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/beta-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 beta-catenin, and upregulation of lymphoid enhancer factor 1 (LEF1) (mediator of Wnt/beta-catenin pathway) and fibronectin (downstream target of Wnt/beta-catenin) in CD2AP-/- podocytes. Total PARylation and active beta-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/beta-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/beta-catenin pathway to treat proteinuric kidney diseases associated with impaired CD2AP.
Subject: FOCAL SEGMENTAL GLOMERULOSCLEROSIS
PLASMINOGEN-ACTIVATOR INHIBITOR-1
CONGENITAL NEPHROTIC SYNDROME
CD2-ASSOCIATED PROTEIN
POLY(ADP-RIBOSE) POLYMERASE
BETA-CATENIN
EMBRYONIC-DEVELOPMENT
ACTIN CYTOSKELETON
LARVAL ZEBRAFISH
STRUCTURAL BASIS
1182 Biochemistry, cell and molecular biology
3111 Biomedicine
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