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Abstract: TH-PO868

Genetic Susceptibility of Diabetic Kidney Disease in Mice Is Linked to a Promoter Variant of XOR

Session Information

Category: Diabetic Kidney Disease

  • 601 Diabetic Kidney Disease: Basic

Authors

  • Daehn, Ilse S., Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Wang, Qin, Icahn School of Medicine at Mount Sinai, New York, New York, United States
  • Qi, Haiying, Mount Sinai school of medicine, Chatham, New Jersey, United States
  • Yu, Liping, Mount Sinai School of Medicine, New York, New York, United States
  • Shi, Shaolin, National Clinical Research Center of Kidney Disease, Jinling Hospital, Nanjing University School of Medicine, Nanjing, JIangSu, China
  • Casalena, Gabriella, Icahn school of medicine at mount sinai, New York, New York, United States
  • Bottinger, Erwin P., Hasso Plattner Insitute, Potsdam, Germany
Background

Diabetic kidney disease (DKD) is the leading single cause of ESRD in the United States. Approximately 10-30% of diabetic patients develop DKD with comparable blood glucose levels, indicating a significant genetic contribution for disease susceptibility. Differential susceptibilities are also observed in well-defined inbred mice strains.
The glomerulus is the primary site of injury with hypertrophy and podocyte depletion being the hallmarks for progressive DKD. We have demonstrated that ROS and mitochondrial oxidative damage accumulation in glomerular endothelial cells (GECs), leads to podocyte loss via endothelial-to-podocyte crosstalk in experimental DKD. However, the underlying mechanisms that contribute to differential susceptibility to DKD are poorly understood.

Methods

Inbred DBA/2J (D2) mice are susceptible, while C57BL/6J (B6) mice resistant to diabetes-induced podocyte depletion. We used the 39 strains of BXD (B6XD2) recombinant inbred and parental strains to map genetic loci associated with podocyte numbers after long-term diabetes (6mth). We identified a cis-acting regulatory (promoter) of the Xdh gene encoding xanthine dehydrogenase XDH/XO (xanthine oxidoreductase (XOR)). XORs catalyze the oxidation of purine substrates, xanthine and hypoxanthine, producing uric acid, and are a major enzymatic source of ROS.

Results

XOR expression in the kidney and XOR circulating activity were significantly increased in diabetic D2 but not B6 mice. XOR inhibition in diabetic D2 mice significantly reduced albuminuria, oxidative damage in glomeruli and prevented podocyte loss.
The two nucleotide variant was shown to influence XOR activity in vitro. To determine whether the variant in XOR promoter underlie the differential responses to diabetes, we used CRISPR/Cas9 to knock-in the XOR variant of D2 into B6 mice. Indeed, the mutant B6-Xor mice had significantly higher XOR activity. These mice developed endothelial injury, with increased ROS and mitochondrial oxidative stress in GECs, podocyte foot process effacement and depletion, basement membrane thickening, albuminuria, glomerular sclerotic lesions and tubular injury, furthermore DKD in B6-Xor mice was prevented with XOR specific inhibition.

Conclusion

These data suggest that the identified promoter variant regulates XOR activity, and may be causal for DKD susceptibility.

Funding

  • NIDDK Support