Endothelial dysfunction represents a predominant early feature of diabetes, rendering patients with diabetes prone to renal complications, e.g., proteinuria. Recent studies indicate a possible role for xanthine oxidase (XO) in the pathogenesis of vascular dysfunctions associated with diabetes. In this study, we investigated the contribution of XO activation on the progression of diabetic nephropathy (DN) in a mouse model using selective XO inhibitors. Male Ins2^Akita heterozygous mice were used with wild-type (WT) mice as controls. Akita mice were treated with Topiroxostat (Topi) or vehicle for 4 weeks. Serum uric acid levels were significantly reduced in Akita+Topi compared with Akita+Vehicle mice. The Akita + Topi group had significant reduction in the urinary albumin excretion in comparison with the Akita + Vehicle group. Mesangial expansion, glomerular collagen IV deposition, and glomerular endothelial injury (assessed by lectin staining and transmission electron microscopy) were considerably reduced in the Akita + Topi group compared with the Akita + Vehicle group. Furthermore, glomerular permeability was significantly higher in the Akita + Vehicle group compared to the WT group. These changes were reduced with the administration of Topi. We conclude that XO inhibitors preserve glomerular endothelial functions and rescue compromised glomerular permeability, suggesting that XO activation plays a vital role in the pathogenesis of DN.

中文翻译：

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非嘌呤选择性黄嘌呤氧化酶抑制剂可减轻 InsAkita 糖尿病小鼠的肾小球内皮损伤。

内皮功能障碍代表了糖尿病的主要早期特征，使糖尿病患者容易出现肾脏并发症，例如蛋白尿。最近的研究表明黄嘌呤氧化酶 (XO) 在与糖尿病相关的血管功能障碍的发病机制中可能发挥作用。在这项研究中，我们使用选择性 XO 抑制剂研究了 XO 激活对小鼠模型糖尿病肾病 (DN) 进展的贡献。男性 Ins2^秋田杂合小鼠与野生型 (WT) 小鼠一起用作对照。秋田小鼠用 Topiroxostat (Topi) 或载体治疗 4 周。与 Akita+Vehicle 小鼠相比，Akita+Topi 小鼠的血清尿酸水平显着降低。与秋田 + 载体组相比，秋田 + Topi 组的尿白蛋白排泄显着减少。与秋田 + 载体组相比，秋田 + Topi 组的系膜扩张、肾小球胶原 IV 沉积和肾小球内皮损伤（通过凝集素染色和透射电子显微镜评估）显着减少。此外，与 WT 组相比，Akita + 载体组的肾小球通透性显着更高。这些变化随着 Topi 的给药而减少。