Tankyrase inhibition aggravates kidney injury in the absence of CD2AP
| Autor: | Kuusela, S, Wang, H, Wasik, A A, Suleiman, H, Lehtonen, S |
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| Přispěvatelé: | Sanna Lehtonen research group, Department of Pathology, Medicum |
| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
Male Cancer Research Poly Adenosine Diphosphate Ribose Embryo Nonmammalian 030232 urology & nephrology POLY(ADP-RIBOSE) POLYMERASE PLASMINOGEN-ACTIVATOR INHIBITOR-1 BETA-CATENIN Podocyte Rats Sprague-Dawley FOCAL SEGMENTAL GLOMERULOSCLEROSIS Mice 0302 clinical medicine Tankyrases Serpin E2 Renal Insufficiency Zebrafish beta Catenin Cell Line Transformed Mice Knockout Kidney Podocytes Wnt signaling pathway ACTIN CYTOSKELETON EMBRYONIC-DEVELOPMENT 3. Good health Cell biology medicine.anatomical_structure Original Article Heterocyclic Compounds 3-Ring Signal Transduction STRUCTURAL BASIS Beta-catenin Lymphoid Enhancer-Binding Factor 1 Immunology Biology Nephropathy 03 medical and health sciences Cellular and Molecular Neuroscience medicine Animals Humans Adaptor Proteins Signal Transducing CD2-ASSOCIATED PROTEIN LARVAL ZEBRAFISH Cell Biology medicine.disease Actin cytoskeleton Molecular biology CONGENITAL NEPHROTIC SYNDROME Fibronectins Rats Cytoskeletal Proteins 030104 developmental biology HEK293 Cells biology.protein 1182 Biochemistry cell and molecular biology Genes Lethal 3111 Biomedicine Protein Processing Post-Translational Lymphoid enhancer-binding factor 1 |
| Zdroj: | Cell Death & Disease |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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