Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan.
Department of Pharmacology, Kagawa University Medical School, Kagawa, Japan.
J Pharmacol Sci. 2020 Dec;144(4):229-236. doi: 10.1016/j.jphs.2020.09.004. Epub 2020 Sep 19.
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.
肾脏是成年人产生促红细胞生成素（EPO）的主要器官，因此，肾脏损伤会导致 EPO 水平降低和贫血。缺氧诱导因子脯氨酰羟化酶结构域蛋白（HIF-PHD）抑制剂有望成为治疗肾性贫血的新方法。可以预测，大多数接受 HIF-PHD 抑制剂治疗的患者因贫血而出现肾功能障碍。因此，在本研究中，我们研究了 HIF-PHD 抑制剂莫立司他在肾性贫血发生后开始时对贫血和肾功能障碍的影响。雄性 C57BL/6J 小鼠口服给予腺嘌呤诱导肾病。肾病发生后，用载体或莫立司他对小鼠进行治疗。给药 4 周后，载体处理的小鼠表现出明显的贫血，而莫立司他改善了这种贫血。载体处理的小鼠表现出肌酐清除率和体重降低、血尿素氮水平升高、组织病理学改变、免疫细胞浸润和脱水。莫立司他逆转了免疫细胞浸润、脱水和肾纤维化，而没有改善肾功能参数。总之，莫立司他在肾病和肾性贫血发生后开始治疗可逆转小鼠的贫血。莫立司他改善了一些肾脏异常参数，但未恢复肾功能。
