NAD deficiency plays essential roles in the hyperuricemia of stroke-prone spontaneously hypertensive rat via xanthine dehydrogenase to xanthine oxidase conversion.

Inhibition of xanthine oxidoreductase (XOR) was shown to ameliorate the stroke susceptibility in the stroke-prone spontaneously hypertensive rat (SHRSP), suggesting hyperuricemia had a pathological role in this rat model. In this study, we thus aimed to explore mechanisms inducing hyperuricemia in SHRSP. XOR is known to have two forms, xanthine dehydrogenase (XDH) as the prototype and xanthine oxidase (XO) as the converted form through cleavage of a peptide bond or through formation of disulfide bonds in the enzyme. XO was shown to have a greater activity to produce UA and oxidative stress. We thus hypothesized that the excess conversion to XO caused the higher UA level in SHRSP. Male SHRSP at 10 weeks of age showed a higher serum level of UA and a higher activity of XO than those in Wistar-Kyoto rat. As the protein level of the total XOR did not differ between the two strains, the conversion to XO seemed responsible for the high UA level in SHRSP. Meanwhile, NAD level in SHRSP was lower than that in WKY, suggesting that low NAD promoted the conversion to XO in this strain. ß-nicotinamide mononucleotide (NMN) supplementation for 2 weeks increased NAD level and reduced the serum UA level as well as the XO activity in SHRSP. These observations supported that a low NAD accelerated the conversion of XDH to XO in SHRSP, which resulted in high UA. The current study suggested the potential significance of NMN supplementation in the treatment of hyperuricemia in humans.