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Tankyrase inhibition aggravates kidney injury in the absence of CD2AP

S Kuusela1, H Wang1, A A Wasik1

  • 1Department of Pathology, University of Helsinki, Helsinki, Finland.

Cell Death & Disease
|July 22, 2016
PubMed

Insights

CD2-associated protein (CD2AP) deficiency in podocytes sustains Wnt/β-catenin signaling, leading to kidney injury. Inhibiting tankyrase PARylation activity in CD2AP deficiency exacerbates kidney damage, highlighting the importance of PARylation balance.

Area of Science:

  • Nephrology
  • Molecular Biology
  • Biochemistry

Background:

  • The Wnt/β-catenin pathway is implicated in podocyte injury and nephropathy.
  • Tankyrases antagonize Wnt/β-catenin signaling and interact with CD2-associated protein (CD2AP).
  • CD2AP is crucial for kidney ultrafiltration; its absence leads to kidney failure.

Purpose of the Study:

  • To investigate the role of tankyrases and CD2AP in podocyte function and kidney injury.
  • To explore the impact of tankyrase inhibition on Wnt/β-catenin signaling and podocyte damage in CD2AP-deficient models.

Main Methods:

  • Analysis of tankyrase-mediated poly(ADP-ribosyl)ation (PARylation) in CD2AP-knockout (CD2AP-/-) mice and cultured podocytes.
  • Assessment of β-catenin activity, LEF1, fibronectin, and PAI-1 expression.
  • Treatment with tankyrase inhibitor XAV939 in CD2AP-/- podocytes and zebrafish models.

Main Results:

  • CD2AP deficiency increased Wnt/β-catenin pathway activation, β-catenin activity, LEF1, and fibronectin in podocytes.
  • XAV939 treatment reduced PARylation and active β-catenin but worsened podocyte injury, increasing LEF1 and PAI-1.
  • XAV939 aggravated kidney injury and mortality in CD2AP-depleted zebrafish.

Conclusions:

  • Sustained Wnt/β-catenin pathway activation in CD2AP-/- podocytes contributes to kidney injury.
  • Inhibiting tankyrase PARylation activity in the absence of CD2AP is detrimental to kidney function.
  • CD2AP-mediated balance of tankyrase PARylation is essential for normal kidney function; targeting Wnt/β-catenin requires careful consideration in CD2AP-impaired kidney diseases.

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