Hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) protects against cisplatin-induced acute kidney injury
Hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) protects against cisplatin-induced acute kidney injury
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缺氧诱导因子脯氨酰羟化酶抑制剂 roxadustat (FG-4592) 可预防顺铂诱导的急性肾损伤
DOI：
10.1042/cs20171625
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发表时间：
2018
期刊：
影响因子：
6
通讯作者：
Zhang Aihua
中科院分区：
文献类型：
--
作者：
Yang Yunwen;Yu Xiaowen;Zhang Yue;Ding Guixia;Zhu Chunhua;Huang Songming;Jia Zhanjun;Zhang Aihua
肾缺氧发生在各种病因的急性肾损伤（阿基）中。低氧诱导转录因子（hypoxia-inducible transcription factor，HIF）的激活是细胞适应低氧环境的重要机制。预条件HIF激活可保护阿基，提示阿基治疗的新方法。HIF在常氧条件下通过HIF脯氨酰羟化酶（PHD）对调节性α-亚基的特定脯氨酰残基的氧依赖性羟基化介导降解。FG-4592是一种新型口服活性小分子HIF PHD抑制剂，用于治疗慢性肾脏病（CKD）患者的贫血。本研究旨在评价FG-4592（Roxadustat）对顺铂诱导的肾损伤的影响。在小鼠中，FG-4592预处理显著改善了顺铂诱导的肾损伤，表现为肾功能（血尿素氮（BUN）、血清肌酐（Scr）和胱抑素C）和肾脏形态（过碘酸-希夫（PAS）染色）改善，与肾小管损伤标志物肾损伤分子1（KIM-1）和中性粒细胞明胶酶相关脂质运载蛋白（NGAL）的强效阻断一致。同时，FG-4592处理的小鼠中顺铂诱导的肾细胞凋亡和炎症也显著减轻。沿着上述保护作用，FG-4592预处理强烈增强肾小管细胞中的HIF-1α，以及HIF靶基因的表达。FG-4592单独给药不影响小鼠肾功能和形态，但在体外可显著上调HIF-1α表达，保护肾小管细胞免受顺铂诱导的凋亡。总之，FG-4592治疗可能通过稳定HIF显著改善顺铂诱导的肾损伤。因此，除了治疗CKD贫血的作用外，FG-4592的临床用途也可扩展至阿基。
Renal hypoxia occurs in acute kidney injury (AKI) of various etiologies. Activation of hypoxia-inducible transcription factor (HIF) has been identified as an important mechanism of cellular adaptation to low oxygen. Preconditional HIF activation protects against AKI, suggesting a new approach in AKI treatment. HIF is degraded under normoxic conditions mediated by oxygen-dependent hydroxylation of specific prolyl residues of the regulative α-subunits by HIF prolyl hydroxylases (PHD). FG-4592 is a novel, orally active, small-molecule HIF PHD inhibitor for the treatment of anemia in patients with chronic kidney disease (CKD). The current study aimed to evaluate the effect of FG-4592 (Roxadustat) oncis-diamminedichloroplatinum (cisplatin)-induced kidney injury. In mice, pretreatment with FG-4592 markedly ameliorated cisplatin-induced kidney injury as shown by the improved renal function (blood urea nitrogen (BUN), serum creatinine (Scr), and cystatin C) and kidney morphology (periodic acid-Schiff (PAS) staining) in line with a robust blockade of renal tubular injury markers of kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL). Meanwhile, the renal apoptosis and inflammation induced by cisplatin were also strikingly attenuated in FG-4592-treated mice. Along with the protective effects shown above, FG-4592 pretreatment strongly enhanced HIF-1α in tubular cells, as well as the expressions of HIF target genes. FG-4592 alone did not affect the renal function and morphology in mice.In vitro, FG-4592 treatment significantly up-regulated HIF-1α and protected the tubular cells against cisplatin-induced apoptosis. In summary, FG-4592 treatment remarkably ameliorated the cisplatin-induced kidney injury possibly through the stabilization of HIF. Thus, besides the role in treating CKD anemia, the clinical use of FG-4592 also could be extended to AKI.