Renoprotective effect of topiroxostat via antioxidant activity in puromycin aminonucleoside nephrosis rats.
Renoprotective effect of topiroxostat via antioxidant activity in puromycin aminonucleoside nephrosis rats.
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DOI：
10.14814/phy2.13358
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发表时间：
2017-08
影响因子：
2.5
通讯作者：
Uchida S
中科院分区：
文献类型：
--
作者：
Kawamorita Y;Shiraishi T;Tamura Y;Kumagai T;Shibata S;Fujigaki Y;Hosoyamada M;Nakagawa T;Uchida S
托吡司他是一种新型的黄嘌呤氧化酶抑制剂，被认为具有肾脏保护作用。嘌呤霉素氨基糖苷肾病（PAN）是一种大鼠微小病变型肾病综合征模型。在这项研究中，我们检查了托吡司他是否改善了PAN大鼠的肾损伤，该肾损伤是由单次腹膜内注射PA（100 mg/kg体重）诱导的。将大鼠分为四组：对照大鼠、PAN大鼠、用托吡司他（1.0mg/kg/天）处理的对照大鼠和用托吡司他处理的PAN大鼠。托吡司他显著降低肾皮质中尿酸的量，而血清UA浓度不受该治疗的影响。托吡司他治疗后，PAN大鼠第10天的尿蛋白排泄量显著降低。PAN大鼠的足细胞损伤，如WT-1阳性细胞数量和podocin免疫反应性减少和足突消失所示，托吡司他治疗部分但显著缓解。在肾皮质中，托吡司他显著改善PAN大鼠中氧化应激标志物如硝基酪氨酸和8-羟基-2-脱氧鸟苷（8-OHdG）的增加以及黄嘌呤氧化酶和NADPH氧化酶4（NOX 4）的表达增强。使用培养的足细胞，通过向培养基中加入12 mg/dL UA来上调N 0X 4表达。这些结果表明，托吡司他通过降低氧化应激和组织UA浓度来改善PAN大鼠的蛋白尿和肾损伤。托吡司他的肾保护作用可能归因于其抑制黄嘌呤氧化酶和NOX 4的潜力，同时抑制细胞内UA的产生。
Topiroxostat is a novel inhibitor of xanthine oxidase, and is postulated to exert a renoprotective effect. Puromycin aminonucleoside nephrosis (PAN) is a rat model of minimal change nephrotic syndrome. In this study, we examined whether topiroxostat ameliorates the kidney injury in PAN rats that was induced by a single intraperitoneal injection of PA (100 mg/kg body weight). Rats were divided into four groups: control rats, PAN rats, control rats treated with topiroxostat (1.0 mg/kg/day), and PAN rats treated with topiroxostat. Topiroxostat significantly reduced the amount of uric acid in the kidney cortex, while serum UA concentration remained unaffected by this treatment. Urinary protein excretion decreased significantly on day 10 in PAN rats upon topiroxostat treatment. Podocyte injury in PAN rats, as indicated by the reduction in WT‐1‐positive cell numbers and podocin immunoreactivity and foot process effacement, was partially yet significantly alleviated with topiroxostat treatment. In the kidney cortex, the increase in oxidative stress markers such as nitrotyrosine and 8‐hydroxy‐2‐deoxyguanosine (8‐OHdG) and the enhanced expressions of xanthine oxidase and NADPH oxidase 4 (NOX4) in PAN rats were significantly ameliorated by topiroxostat. Using cultured podocytes NOX4 expression was upregulated by adding 12 mg/dL UA into the culture medium. These results suggest that topiroxostat ameliorates proteinuria and kidney injury in PAN rats by lowering oxidative stress and tissue UA concentration. The renoprotective effects of topiroxostat could be attributed to its potential to inhibit xanthine oxidase and NOX4 in concert with suppression of intracellular UA production.