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182-OR: Genetic Susceptibility to Diabetic Kidney Disease Is Linked to C/EBP-XOR Axis

Diabetic kidney disease (DKD) is the leading single cause of end-stage renal disease in the United States. Approximately 30% of diabetics develop DKD with comparable blood glucose levels, indicating a significant genetic contribution for susceptibility. However, the underlying mechanisms that contribute to differential susceptibility are poorly understood. The glomerulus is the primary site of injury with hypertrophy and podocyte depletion being the hallmarks for progressive DKD. We have demonstrated that mitochondrial oxidative damage accumulation in glomerular endothelial cells, leads to podocyte loss via endothelial-to-podocyte crosstalk in DKD susceptible DBA/2J (D2) mice compared to DKD resistant C57BL/6J (B6) mice. To map genetic loci associated with podocyte depletion after long-term diabetes (6mth), we used the 39 strains of BXD, and parental B6 and D2 mice. We identified a significant cis-acting variant in the promoter of xanthine oxidoreductase (XOR). XORs catalyze the oxidation of purine substrates produce uric acid and reactive oxygen species. XOR expression in the kidney and circulating activity were significantly higher in diabetic D2 compared to B6. XOR inhibition significantly reduced albuminuria, oxidative damage in glomeruli and prevented podocyte depletion in diabetic D2 mice. We used CRISPR/Cas9 to knock-in the XOR risk variant into DKD-resistant B6 mice and generated mutant B6-XORem1 mice with significantly higher XOR activity than B6. This risk variant is a transcription factor binding site to C/EBPβ, we show higher C/EBPβ expression in glomerular endothelium from diabetic B6-XORem1 mice but not in diabetic B6. B6-XORem1 mice had increased mitochondrial oxidative stress in endothelial cells, podocyte depletion, basement membrane thickening, albuminuria, glomerulosclerosis and tubular injury, and these changes were prevented with XOR inhibition. Our data suggest that the identified promoter variant is causal for DKD susceptibility via the C/EBPβ-XOR axis. Disclosure Q. Wang: None. H. Qi: None. S. Li: None. G. Casalena: None. L. Yu: None. I. S. Daehn: None. Funding National Institutes of Health