Lack of xanthine dehydrogenase leads to a remarkable renal decline in a novel hypouricemic rat model
Lashodya V. Dissanayake,
Adrian Zietara,
Vladislav Levchenko,
Denisha R. Spires,
Mariana Burgos Angulo,
Ashraf El-Meanawy,
Aron M. Geurts,
Melinda R. Dwinell,
Oleg Palygin,
Alexander Staruschenko
Affiliations
Lashodya V. Dissanayake
Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, 560 Channelside Dr., Tampa, FL 33602, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Adrian Zietara
Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, 560 Channelside Dr., Tampa, FL 33602, USA; Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Vladislav Levchenko
Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, 560 Channelside Dr., Tampa, FL 33602, USA
Denisha R. Spires
Department of Physiology, Medical College of Georgia, Augusta University, Augusta, GA 30912, USA
Mariana Burgos Angulo
Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, 560 Channelside Dr., Tampa, FL 33602, USA
Ashraf El-Meanawy
Division of Nephrology, Department of Medicine, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Aron M. Geurts
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Melinda R. Dwinell
Department of Physiology, Medical College of Wisconsin, Milwaukee, WI 53226, USA
Oleg Palygin
Department of Medicine, Division of Nephrology, Medical University of South Carolina, Charleston, SC 29425, USA; Department of Regenerative Medicine and Cell Biology, Medical University of South Carolina, Charleston, SC 29425, USA
Alexander Staruschenko
Department of Molecular Pharmacology & Physiology, Morsani College of Medicine, University of South Florida, 560 Channelside Dr., Tampa, FL 33602, USA; Hypertension and Kidney Research Center, University of South Florida, Tampa, FL 33602, USA; James A. Haley Veterans' Hospital, Tampa, FL 33612, USA; Corresponding author
Summary: 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 (SSXdh−/−). SSXdh−/− 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.
