Effects of post-renal anemia treatment with the HIF-PHD inhibitor molidustat on adenine-induced renal anemia and kidney disease in mice
Effects of post-renal anemia treatment with the HIF-PHD inhibitor molidustat on adenine-induced renal anemia and kidney disease in mice
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DOI：
10.1016/j.jphs.2020.09.004
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发表时间：
2020-12-01
影响因子：
3.5
通讯作者：
Nishiyama, Akira
中科院分区：
文献类型：
--
作者：
Li, Lei;Nakano, Daisuke;Nishiyama, Akira
肾脏是成年人产生促红细胞生成素（EPO）的主要器官，因此，肾脏损伤导致EPO水平降低和贫血。低氧诱导因子-脯氨酰羟化酶结构域抑制剂（HIF-PHD）有望成为肾性贫血的新的治疗选择。可以预测，大多数接受HIF-PHD抑制剂的患者都有肾功能不全，这是贫血的原因。因此，在本研究中，我们研究了在肾性贫血发作后开始使用HIF-PHD抑制剂莫度司他对贫血和肾功能不全的影响。雄性C57 BL/6 J小鼠口服腺嘌呤以诱导肾病。在肾病发作后，用媒介物或莫利度他处理小鼠。给药4周后，溶媒处理的小鼠显示出明显的贫血，而莫利度他改善了这种贫血。溶剂处理小鼠表现出肌酐清除率和体重降低、血尿素氮水平升高、组织病理学变化、免疫细胞浸润和脱水。Molidustat逆转了免疫细胞浸润、脱水和肾纤维化，但未改善肾功能参数。总之，在肾病和肾性贫血发作后开始的Molidustat治疗逆转了小鼠的贫血。Molidustat改善了肾脏异常的一些参数，但不能恢复肾功能。(C)2020年，任作家。Elsevier B. V.代表日本药理学会制作和主办。这是一个CC BY-NC-ND许可下的开放获取文章。
The kidneys are the major organs for erythropoietin (EPO) production in adults, and thus, kidney damage results in reduced EPO levels and anemia. Inhibitors of Hypoxia-inducible factor-prolyl hydroxylase domain-containing protein (HIF-PHD) are awaited as new therapeutic options for renal anemia. It can be predicted that most patients who receive HIF-PHD inhibitors have renal dysfunction as a cause of anemia. Therefore, in the present study, we investigated the effects of the HIF-PHD inhibitor molidustat on anemia and renal dysfunction when initiated after the onset of renal anemia. Male C57BL/6J mice received adenine orally to induce nephropathy. After the onset of nephropathy, the mice were treated with either vehicle or molidustat. After 4 weeks of administration, vehicle-treated mice displayed significant anemia, and molidustat ameliorated this anemia. Vehicle-treated mice exhibited reduced creatinine clearance and body weight, increased blood urea nitrogen levels, histopathological changes, immune cell infiltration, and dehydration. Molidustat reversed immune cell infiltration, dehydration, and renal fibrosis without improving renal functional parameters. In conclusion, molidustat treatment initiated after the onset of nephropathy and renal anemia reversed anemia in mice. Molidustat improved some parameters of renal abnormality, but it did not restore renal function. (C) 2020 The Authors. Production and hosting by Elsevier B.V. on behalf of Japanese Pharmacological Society. This is an open access article under the CC BY-NC-ND license.