Tankyrase inhibition aggravates kidney injury in the absence of CD2AP

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.

Tankyrase inhibition ameliorates lipid disorder via suppression of PGC-1α PARylation in db/db mice

“…Both TNKS1 and TNKS2 are expressed in WAT in db/db and db/+ mice ( Fig. S4A), migrating at 160 kDa and 130 kDa, respectively, as previously demonstrated by transient overexpression in HEK293 cells [20]. G007-LK reduced the protein level of TNKS1 and TNKS2 in WAT in both genotypes ( Fig.…”

“…TNKS-mediated PARylation depends on the sequence of the TNKS-binding motif and the structural features of the binding partner [ 19 ]. Consequently, not all binding partners become PARylated [ 19 ], and some even inhibit the PARylation activity of TNKSs [ 20 ]. In humans, TNKS (the gene encoding tankyrase 1, TNKS1) localizes to chromosome 8p23.1, a susceptibility locus for T2DM [ 21 ], and variants of TNKS associate with early-onset obesity [ 22 ].…”

Inhibition of SHIP2 in CD2AP-deficient podocytes ameliorates reactive oxygen species generation but aggravates apoptosis

“…In CD2AP−/− podocytes, SHIP2 inhibition did reduce ROS but aggravated apoptosis. Resembling this, we observed previously increased activity of β-catenin in podocytes in the absence of CD2AP, but found that inhibition of the Wnt/β-catenin pathway did not ameliorate but further aggravated kidney injury 41 . These data reinforce the central role of CD2AP as a regulator of multiple pathways in podocytes and reveal that inhibition of the harmful pathways may have unexpected adverse effects.…”

Novel insight into the function of tankyrase (Review)

“…Podocyte damage results in numerous glomerular diseases, including nephritic syndrome and nephrotic syndrome ( 87 ). Kuusela et al ( 30 ) demonstrated that tankyrases interact with CD2AP, and CD2AP is a negative tankyrase regulator. Tankyrase inhibition in the absence of CD2AP increases kidney damage, which indicates that tankyrases are essential for maintaining normal kidney function ( 87 ).…”