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Kidney Week

Abstract: TH-OR067

Tankyrase Inhibition Upregulates Mitochondrial Master Regulator PGC-1α in the Kidney of db/db Mice

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic


  • Kuusela, Sara, University of Helsinki, Helsinki, Finland
  • Wang, Hong, University of Helsinki, Helsinki, Finland
  • Lehtonen, Eero, University of Helsinki, Helsinki, Finland
  • Dumont, Vincent, University of Helsinki, Helsinki, Finland
  • Waaler, Jo, Oslo University Hospital, Oslo, Norway
  • Chi, Nai-Wen, UC San Diego, La jolla, California, United States
  • Lehtonen, Sanna H., University of Helsinki, Helsinki, Finland

Mitochondrial oxidative stress contributes to the cellular damage occurring in diabetic conditions. Peroxisome proliferator-activated receptor γ (PPARγ) coactivator 1α (PGC-1α) co-activates transcription factors that boost mitochondrial biogenesis and oxidative metabolism and interestingly, PGC-1α is downregulated in the kidney in diabetes. Tankyrase 1 and 2 (TNKS1 and TNKS2) are closely related homologs belonging to the poly-ADP-ribose-polymerase (PARP) family of proteins. TNKSs regulate their binding partners by post-translational modification (PARylation), typically increasing protein degradation. The aim of this study was to investigate whether pharmacological inhibition of TNKSs in db/db mice protects against kidney injury by regulating PGC-1α.


We treated 6 weeks old obese and diabetic db/db and non-diabetic db/+ controls with the TNKS1/TNKS2-specific inhibitor G007-LK with 14 mg/kg/day dosing for 15 weeks and investigated the effect on systemic and kidney parameters.


We found that TNKS inhibition reduces body weight gain and fat mass, and upregulates genes associated with β-oxidation in muscle in db/db mice. In cultured C2C12 myocytes TNKS inhibition stimulated fatty acid oxidation and impoved mitochondrial function. TNKS inhibitor treatment reduced glomerular area in the db/db mice albeit the albuminuria was not alleviated. Proximity ligation assay indicated that PGC-1α and TNKSs form a complex in the kidney cortex and that PGC-1α PARylation is decreased upon TNKS inhibition in renal tubules. This apparently increased the stability of PGC-1α leading to its upregulation. Additionally, immunoblotting of mitochondrial respiratory chain markers indicated that TNKS inhibition upregulates complex V ATP synthase subunit alpha (ATP5A) in db/db kidney cortices. Electron microscopy analysis of proximal tubule cells revealed that TNKS inhibitor treatment upregulates crista density of mitochondria. These data indicate that TNKS inhibition increases mitochondrial respiration rate.


We found that TNKS inhibition increases PGC-1α expression and improves oxidative metabolism. Along with existing clinical approaches, enhancing mitochondrial function by TNKS inhibition could offer an additional strategy to improve renal structural and functional parameters in diabetes.