Wan Xulian, Yun Yu, Li Shixiong, Luo Guanyun, Li Ning, Yin Hua, Duan Weigang
School of Basic Medicine, Yunnan University of Chinese Medicine, Kunming, Yunnan, China.
School of Basic Medicine, Kunming Medical University, Kunming, Yunnan, China.
PLoS One. 2025 Aug 22;20(8):e0330344. doi: 10.1371/journal.pone.0330344. eCollection 2025.
Clinical evidence suggests that hyperuricemia is frequently associated with hyperglycemia (diabetes), hyperlipidemia, and hypertension. However, this relationship has not been fully verified in experimental animals. The present study used uricase-deficient rats (KDY rats, n = 125) with spontaneously elevated levels of serum uric acid (SUA) as the model animals and investigated their metabolic conditions throughout their lifespan (626 days of age). The serum, urine and feces of the rats were collected, histological examination was performed using hematoxylin-eosin or Masson's staining, and gene expression was determined using transcriptome high-throughput sequencing. Compared with wild type (WT) rats of the same age, the SUA levels in KDY rats were continuously high (approximately 70 μg/mL), and the body weight gain slowed after 45 days of age, followed by increased urine output, diabetes mellitus (hyperglycemia), high low-density lipoprotein, and hypercholesterolemia. Histological examination showed that gouty nephropathy appeared after approximately 45 days of age, before the rats developed medullary injury, medullary interstitial fibrosis, cortical glomerulus injury, and glomerular fibrosis. KDY rats also showed signs of atherosclerosis and hypertension in the late stage of their lifespan. The lifespan of KDY rats was significantly shorter than that of WT rats (more than 626 days). The expected lifespan of KDY rats is approximately 450 days, and the direct cause of the shortened lifespan is renal failure caused by gout nephropathy. The direct mechanisms of the lesions in KDY are related to the upregulation of various of inflammatory (immune) pathways. In conclusion, it demonstrated that hyperuricemia in KDY rats leads to type 2 diabetes mellitus (hyperglycemia), hyperlipidemia, atherosclerosis, and hypertension, in addition to gouty nephropathy.
临床证据表明，高尿酸血症常与高血糖（糖尿病）、高脂血症和高血压相关。然而，这种关系在实验动物中尚未得到充分验证。本研究使用血清尿酸（SUA）水平自发升高的尿酸酶缺陷大鼠（KDY大鼠，n = 125）作为模型动物，研究其整个生命周期（626日龄）的代谢状况。收集大鼠的血清、尿液和粪便，采用苏木精-伊红或Masson染色进行组织学检查，并使用转录组高通量测序测定基因表达。与同年龄的野生型（WT）大鼠相比，KDY大鼠的SUA水平持续较高（约70μg/mL），45日龄后体重增加减缓，随后尿量增加、患糖尿病（高血糖）、低密度脂蛋白升高和高胆固醇血症。组织学检查显示，约45日龄后出现痛风性肾病，随后大鼠出现髓质损伤、髓质间质纤维化、皮质肾小球损伤和肾小球纤维化。KDY大鼠在其生命周期后期还表现出动脉粥样硬化和高血压的迹象。KDY大鼠的寿命明显短于WT大鼠（超过626天）。KDY大鼠的预期寿命约为450天，寿命缩短的直接原因是痛风性肾病导致的肾衰竭。KDY大鼠病变的直接机制与多种炎症（免疫）途径的上调有关。总之，研究表明KDY大鼠的高尿酸血症除了导致痛风性肾病外，还会导致2型糖尿病（高血糖）、高脂血症、动脉粥样硬化和高血压。
