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CRISPR/Cas9 Mediated Deletion of the Uox Gene Generates a Mouse Model of Hyperuricemia with Multiple Complications
Linzi Zeng1, Shalaimaiti Shali2,3,4, Yabiao Gao1
1Department of Physiology and Pathophysiology of School of Basic Medical Sciences, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.
Abstract:
Hyperuricemia is a common metabolic disorder with severe complications. We aimed to develop a mouse model for spontaneous hyperuricemia. Uox-/- mouse model was generated on C57BL/6J background by deleting exon 2-4 of Uox using the CRISPR/Cas9 system. The prototypic Uox -/-mice had 5.5-fold increased serum uric acid (1351.04±276.58μmol/L) as compared to the wild type mice (P<0.0001), but died by 4 weeks. After allopurinol (3ug/g) intervention, they all survived > 8 weeks. The serum uric acid was 612.55±146.98μmol/L in the 8-week-old allopurinol-rescued Uox -/-mice, which manifested multiple complications including severe renal insufficiency, hypertension, left ventricular remodeling and systolic dysfunction, aortic endothelial dysfunction, hepatic steatosis and elevated liver enzymes, as well as hyperglycemia and hypercholesteremia. The present Uox-/- mice developed spontaneous hyperuricemia complicated with urate nephropathy, cardiovascular disease and cardiometabolic disorders, and may provide a novel tool to study hyperuricemia associated early-onset cardiovascular disorders in human.
Insights
Researchers developed a novel mouse model for spontaneous hyperuricemia. This model exhibits complications like kidney disease and cardiovascular issues, aiding research into metabolic disorders.
Area of Science:
- Biomedical Research
- Metabolic Disorders
- Animal Models
Background:
- Hyperuricemia is a prevalent metabolic disorder with significant health implications.
- Existing models may not fully capture the complexity of spontaneous hyperuricemia and its associated conditions.
Purpose of the Study:
- To create a mouse model that spontaneously develops hyperuricemia.
- To investigate the complications arising from sustained high uric acid levels in this model.
Main Methods:
- Utilized CRISPR/Cas9 gene editing to delete exons 2-4 of the Uox gene in C57BL/6J mice, creating Uox-/- mice.
- Administered allopurinol to rescue lethality and assess long-term complications in surviving Uox-/- mice.
Main Results:
- Uox-/- mice exhibited a 5.5-fold increase in serum uric acid and early mortality.
- Allopurinol-rescued Uox-/- mice (surviving > 8 weeks) developed severe renal insufficiency, hypertension, cardiac dysfunction, aortic endothelial dysfunction, hepatic steatosis, hyperglycemia, and hypercholesterolemia.
- These findings demonstrate spontaneous hyperuricemia complicated by urate nephropathy, cardiovascular disease, and cardiometabolic disorders.
Conclusions:
- The developed Uox-/- mouse model recapitulates spontaneous hyperuricemia with multifaceted complications.
- This model serves as a valuable tool for studying early-onset cardiovascular and cardiometabolic disorders associated with hyperuricemia in humans.
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