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) on cis-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.
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A representation of the intestinal microflora. In Clinical Science volume 132 (issue 7), Rajani and Jia review recent research on the effect of bacterial metabolites on host metabolism (microbiota-host co-metabolism) associated with conditions such as obesity, cardiovascular disease, diabetes and non-alcoholic fatty liver disease (pages 791-811). Then, in issue 8, Lezutekong et al. (pages 901-904) provide a commentary on a recent research by Kim et al. in Clinical Science that demonstrates a crucial link between gut microbiota and bacterial metabolites such as butyrate, gut leakiness, and hypertension. These and other articles from the journal are featured in a themed collection on the topic of the microbiome and chronic disease.
Research Article|
April 16 2018
Hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) protects against cisplatin-induced acute kidney injury
Yunwen Yang;
Yunwen Yang
*
1Department of Nephrology, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, China
2Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China
3Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing 210008, China
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Xiaowen Yu;
Xiaowen Yu
*
1Department of Nephrology, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, China
2Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China
3Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing 210008, China
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Yue Zhang;
Yue Zhang
1Department of Nephrology, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, China
2Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China
3Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing 210008, China
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Guixia Ding;
Guixia Ding
1Department of Nephrology, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, China
2Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China
3Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing 210008, China
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Chunhua Zhu;
Chunhua Zhu
1Department of Nephrology, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, China
2Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China
3Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing 210008, China
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Songming Huang;
Songming Huang
1Department of Nephrology, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, China
2Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China
3Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing 210008, China
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Zhanjun Jia;
1Department of Nephrology, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, China
2Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China
3Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing 210008, China
Correspondence: Aihua Zhang ([email protected]) or Zhanjun Jia ([email protected])
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Aihua Zhang
1Department of Nephrology, Children’s Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, China
2Jiangsu Key Laboratory of Pediatrics, Nanjing Medical University, Nanjing 210029, China
3Nanjing Key Laboratory of Pediatrics, Children’s Hospital of Nanjing Medical University, Nanjing 210008, China
Correspondence: Aihua Zhang ([email protected]) or Zhanjun Jia ([email protected])
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Publisher: Portland Press Ltd
Received:
December 14 2017
Revision Received:
March 14 2018
Accepted:
March 26 2018
Accepted Manuscript online:
March 26 2018
Online ISSN: 1470-8736
Print ISSN: 0143-5221
© 2018 The Author(s). Published by Portland Press Limited on behalf of the Biochemical Society
2018
Clin Sci (Lond) (2018) 132 (7): 825–838.
Article history
Received:
December 14 2017
Revision Received:
March 14 2018
Accepted:
March 26 2018
Accepted Manuscript online:
March 26 2018
Citation
Yunwen Yang, Xiaowen Yu, Yue Zhang, Guixia Ding, Chunhua Zhu, Songming Huang, Zhanjun Jia, Aihua Zhang; Hypoxia-inducible factor prolyl hydroxylase inhibitor roxadustat (FG-4592) protects against cisplatin-induced acute kidney injury. Clin Sci (Lond) 16 April 2018; 132 (7): 825–838. doi: https://doi.org/10.1042/CS20171625
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