Lack of xanthine dehydrogenase leads to a remarkable renal decline in a novel hypouricemic rat model

Uric acid (UA) is the final metabolite in purine catabolism in humans. Previous studies have shown that the dysregulation of UA homeostasis is detrimental to cardiovascular and kidney health. The Xdh gene encodes for the Xanthine Oxidoreductase enzyme group, responsible for producing UA. To explore how hypouricemia can lead to kidney damage, we created a rat model with the genetic ablation of the Xdh gene on the Dahl salt-sensitive rat background (SS(Xdh−/−)). SS(Xdh−/−) rats lacked UA and exhibited impairment in growth and survival. This model showed severe kidney injury with increased interstitial fibrosis, glomerular damage, crystal formation, and an inability to control electrolyte balance. Using a multi-omics approach, we highlighted that lack of Xdh leads to increased oxidative stress, renal cell proliferation, and inflammation. Our data reveal that the absence of Xdh leads to kidney damage and functional decline by the accumulation of purine metabolites in the kidney and increased oxidative stress.