Open AccessAnti-anemia drug FG4592 retards the AKI-to-CKD transition by improving vascular regeneration and antioxidative capability
Author(s) -
Mengqiu Wu,
Weiyi Chen,
Mengqiu Miao,
Qianqian Jin,
Shengnan Zhang,
Mei Bai,
Jinhui Fan,
Yue Zhang,
Aihua Zhang,
Zhanjun Jia,
Songming Huang
Publication year - 2021
Publication title -
clinical science
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.91
H-Index - 138
eISSN - 1470-8736
pISSN - 0143-5221
DOI - 10.1042/cs20210100
Subject(s) - sod2 , kidney disease , medicine , acute kidney injury , kidney , hypoxia inducible factors , vascular endothelial growth factor , hypoxia (environmental) , vascular endothelial growth factor a , pharmacology , ischemia , endocrinology , superoxide dismutase , oxidative stress , biology , chemistry , vegf receptors , biochemistry , organic chemistry , oxygen , gene
Acute kidney injury (AKI) is a known risk factor for the development of chronic kidney disease (CKD), with no satisfactory strategy to prevent the progression of AKI to CKD. Damage to the renal vascular system and subsequent hypoxia are common contributors to both AKI and CKD. Hypoxia-inducible factor (HIF) is reported to protect the kidney from acute ischemic damage and a novel HIF stabilizer, FG4592 (Roxadustat), has become available in the clinic as an anti-anemia drug. However, the role of FG4592 in the AKI-to-CKD transition remains elusive. In the present study, we investigated the role of FG4592 in the AKI-to-CKD transition induced by unilateral kidney ischemia–reperfusion (UIR). The results showed that FG4592, given to mice 3 days after UIR, markedly alleviated kidney fibrosis and enhanced renal vascular regeneration, possibly via activating the HIF-1α/vascular endothelial growth factor A (VEGFA)/VEGF receptor 1 (VEGFR1) signaling pathway and driving the expression of the endogenous antioxidant superoxide dismutase 2 (SOD2). In accordance with the improved renal vascular regeneration and redox balance, the metabolic disorders of the UIR mice kidneys were also attenuated by treatment with FG4592. However, the inflammatory response in the UIR kidneys was not affected significantly by FG4592. Importantly, in the kidneys of CKD patients, we also observed enhanced HIF-1α expression which was positively correlated with the renal levels of VEGFA and SOD2. Together, these findings demonstrated the therapeutic effect of the anti-anemia drug FG4592 in preventing the AKI-to-CKD transition related to ischemia and the redox imbalance.