Ferdaus Sara Amelia, Ohara Hiroki, Matsuo Hiroyuki, Kawakami Kohei, Takeuchi Fumihiko, Fujikawa Koichi, Kawakita Emi, Kato Norihiro, Nabika Toru, Kanasaki Keizo
Department of Internal Medicine 1, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan.
Department of Functional Pathology, Shimane University Faculty of Medicine, 89-1 Enya-cho, Izumo, Shimane, 693-8501, Japan.
Biochem Biophys Res Commun. 2025 Jan;744:151136. doi: 10.1016/j.bbrc.2024.151136. Epub 2024 Dec 12.
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.
黄嘌呤氧化还原酶（XOR）的抑制作用已被证明可改善易中风自发性高血压大鼠（SHRSP）的中风易感性，这表明高尿酸血症在该大鼠模型中具有病理作用。因此，在本研究中，我们旨在探索SHRSP中诱导高尿酸血症的机制。已知XOR有两种形式，即原型的黄嘌呤脱氢酶（XDH）和通过肽键断裂或酶中二硫键形成而转化的黄嘌呤氧化酶（XO）。已证明XO产生尿酸（UA）和氧化应激的活性更高。因此，我们假设向XO的过度转化导致了SHRSP中较高的UA水平。10周龄的雄性SHRSP血清UA水平和XO活性高于Wistar-Kyoto大鼠。由于两种品系之间总XOR的蛋白质水平没有差异，因此向XO的转化似乎是SHRSP中高UA水平的原因。同时，SHRSP中的烟酰胺腺嘌呤二核苷酸（NAD）水平低于WKY大鼠，这表明低NAD促进了该品系向XO的转化。补充β-烟酰胺单核苷酸（NMN）2周可提高SHRSP中的NAD水平，并降低血清UA水平以及XO活性。这些观察结果支持低NAD加速了SHRSP中XDH向XO的转化，从而导致高UA。当前的研究表明补充NMN在治疗人类高尿酸血症方面具有潜在意义。
