Xanthine oxidoreductase is an endogenous regulator of cyclooxygenase-2.
Xanthine oxidoreductase (XOR) is the enzyme responsible for the final step in purine degradation resulting in the generation of uric acid. Here we have generated mice deficient in XOR. As expected, these animals lack tissue XOR activity and have low to undetectable serum levels of uric acid. Although normal at birth, XOR-/- mice fail to thrive after 10 to 14 days, and most die within the first month. The cause of death appears to be a form of severe renal dysplasia, a phenotype that closely resembles what has been observed previously in cyclooxygenase-2 (COX-2)-deficient mice. We further demonstrate that in the first month of life, a period in which the mouse kidney is undergoing rapid maturation and remodeling, wild-type mice exhibit an approximately 30-fold increase in renal XOR activity, with a corresponding induction of COX-2 expression. In contrast, during this same period, XOR-/- animals fail to augment renal COX-2 expression. Finally, we show that in vitro and in vivo, uric acid can stimulate basal COX-2 expression. These results demonstrate that XOR activity is an endogenous physiological regulator of COX-2 expression and thereby provide insight into previous epidemiological evidence linking elevated serum uric levels with systemic hypertension and increased mortality from cardiovascular diseases. In addition, these results suggest a novel molecular link between cellular injury and the inflammatory response.
Ohtsubo
Toshio
T
Cardiovascular Branch, National Heart, Lung, and Blood Institute, NIH, Bethesda, Md 20892-1622, USA.
Rovira
Ilsa I
II
Starost
Matthew F
MF
Liu
Chengyu
C
Finkel
Toren
T
D000818:Animals; D001806:Blood Urea Nitrogen; D051546:Cyclooxygenase 2; D018450:Disease Progression; D004790:Enzyme Induction; D005260:Female; D005804:Genes, Lethal; D018740:Genetic Heterogeneity; D006973:Hypertension / Q000097:blood / Q000201:enzymology; D007249:Inflammation; D007668:Kidney / Q000201:enzymology* / Q000473:pathology; D007674:Kidney Diseases / Q000097:blood / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D041681:NIH 3T3 Cells / Q000201:enzymology; D010641:Phenotype; D011451:Prostaglandin-Endoperoxide Synthases / Q000096:biosynthesis* / Q000235:genetics; D014527:Uric Acid / Q000494:pharmacology; D014969:Xanthine Oxidase / Q000172:deficiency / Q000235:genetics / Q000502:physiology*
D014527:Uric Acid; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D014969:Xanthine Oxidase