TY - JOUR
T1 - Tankyrase inhibition aggravates kidney injury in the absence of CD2AP
AU - Kuusela, S.
AU - Wang, H.
AU - Wasik, A. A.
AU - Suleiman, H.
AU - Lehtonen, S.
N1 - Funding Information:
Acknowledgements. We thank Dr. Susan Smith (New York University School of Medicine, New York, NY) for tankyrase 1 construct and Dr. Nai-Wen Chi (University of California, San Diego, La Jolla, CA) for tankyrase 2 construct. We thank Dr. Andrey Shaw (Washington University, School of Medicine, St. Louis, MO) for CD2AP − / − and WT mouse kidney samples and the podocyte cells lines. Niina Ruoho and Henri Koivula (University of Helsinki, Helsinki, Finland) are thanked for skillful technical assistance. Biomedicum Imaging Unit (University of Helsinki, Helsinki, Finland) is acknowledged for help with confocal microscopy. This work was supported by the European Research Council (242820; SL), the Academy of Finland (131255, 218021, 255551; SL), the Sigrid Jusélius Foundation (SL), the Päivikki and Sakari Sohlberg Foundation (SL), the Diabetes Research Foundation (SL), the Faculty of Medicine, University of Helsinki (SL), the Finnish Cultural Foundation (SK) and the Finnish Kidney Foundation (SK).
PY - 2016
Y1 - 2016
N2 - 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-(ADPribosyl) 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.
AB - 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-(ADPribosyl) 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.
UR - http://www.scopus.com/inward/record.url?scp=84986279789&partnerID=8YFLogxK
U2 - 10.1038/cddis.2016.217
DO - 10.1038/cddis.2016.217
M3 - Article
C2 - 27441654
AN - SCOPUS:84986279789
SN - 2041-4889
VL - 7
JO - Cell Death and Disease
JF - Cell Death and Disease
IS - 7
M1 - A2412
ER -