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.
Highlights
The glomerular filtration barrier consists of fenestrated endothelial cells, glomerular basement membrane and glomerular epithelial cells or podocytes
We show that CD2-associated protein (CD2AP) interacts with tankyrase 1 and tankyrase 2, and that in the absence of CD2AP tankyrase-mediated total PARylation in podocytes is increased
Podocytes lacking CD2AP accumulate active β-catenin leading to upregulation of LEF1 and fibronectin, both associated with podocyte injury
Summary
The glomerular filtration barrier consists of fenestrated endothelial cells, glomerular basement membrane and glomerular epithelial cells or podocytes. Treatment with tankyrase inhibitor, Wnt/β-catenin pathway antagonist XAV939, had no effect on TCF-1, TCF-3 or TCF-4 expression; it significantly increased Lef[1] expression in CD2AP − / − podocytes (Figure 5l).
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