Deletion of the Uox gene generates a mouse model of hyperuricemia with cardiovascular complications

Abstract Background/introductions: Hyperuricemia is associated with hypertension, coronary atherosclerosis and heart failure. However, the causal relationship between uric acid (UA) and cardiovascular disease remains controversial. There has been lack of mouse model for spontaneous hyperuricemia with cardiovascular complications. Purpose We aimed to develop urate oxidase (Uox) deficient mice with hyperuricemia that can survive to adulthood. Methods Uox-knockout mouse model was generated on C57BL/6J background by deleting exon 2-4 of Uox using the CRISPR/Cas9 system. we evaluated the hyperuricemic phenotypes regarding magnitude of serum UA elevation, cardiometabolic abnormalities, and cardiovascular complications. Results The birth rate of homozygous Uox-knockout (Uox -/-) mice was 21.4%. The prototypic Uox -/-mice had 5.5-fold increased serum uric acid (1351.04±276.58 μmol/L) as compared to the wild type mice (P<0.0001)), but mostly died by four weeks. After allopurinol (3ug/g) intervention, they all survived more than eight weeks (median: 12.6 weeks, range:9.6 to 16.0 weeks). The serum UA was 612.55±146.98μmol/L (2.5 times higher than that in WT mice, P<0.0001) in the eight-week-old allopurinol-rescued Uox -/-mice, which also manifested multiple complications including hypertension (systolic blood pressure:155.25±9.48mmHg vs. 109.53±11.02mmHg, P<0.0001), left ventricular remodeling and systolic dysfunction (all echocardiographic functional parameters, P<0.001), aortic endothelial cell impairment (P<0.001 for proliferating cell nuclear antigen and ZO-1, P=0.027 for VE-cadherin), hepatic steatosis and elevated liver enzymes (all enzymes P<0.0001), as well as urate nephropathy, hyperglycemia (P=0.0146 for fasting glucose) and hypercholesteremia (P=0.0045 for total cholesterol). Conclusion The present Uox-/- mice developed spontaneous hyperuricemia complicated with cardiovascular disease and cardiometabolic disorders. This allopurinol-rescued Uox-/- mouse model could survive to adulthood, and may provide a novel tool to study urate biology and hyperuricemia associated early-onset disorders in human. Figure 1 Figure 2