Department of Nephrology, Children's Hospital of Nanjing Medical University, 72 Guangzhou Road, Nanjing 210008, China.
Nanjing Key Laboratory of Pediatrics, Children's Hospital of Nanjing Medical University, Nanjing 210008, China.
Clin Sci (Lond). 2021 Jul 30;135(14):1707-1726. doi: 10.1042/CS20210100.
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.
急性肾损伤 (AKI) 是慢性肾脏病 (CKD) 发展的已知危险因素，目前尚无令人满意的策略来防止 AKI 进展为 CKD。肾血管系统损伤和随后的缺氧是 AKI 和 CKD 的共同致病因素。缺氧诱导因子 (HIF) 被报道可保护肾脏免受急性缺血性损伤，一种新型 HIF 稳定剂 FG4592（罗沙司他）已在临床上作为抗贫血药物使用。然而，FG4592 在 AKI 向 CKD 转变中的作用仍不清楚。在本研究中，我们研究了 FG4592 在单侧肾缺血再灌注 (UIR) 诱导的 AKI 向 CKD 转变中的作用。结果表明，FG4592 在 UIR 后 3 天给予小鼠，可显著减轻肾脏纤维化并增强肾脏血管再生，可能通过激活 HIF-1α/血管内皮生长因子 A (VEGFA)/血管内皮生长因子受体 1 (VEGFR1) 信号通路并驱动内源性抗氧化超氧化物歧化酶 2 (SOD2) 的表达。与改善的肾脏血管再生和氧化还原平衡一致，FG4592 治疗还减轻了 UIR 小鼠肾脏的代谢紊乱。然而，FG4592 对 UIR 肾脏的炎症反应没有明显影响。重要的是，在 CKD 患者的肾脏中，我们还观察到增强的 HIF-1α 表达，其与肾脏中 VEGFA 和 SOD2 的水平呈正相关。总之，这些发现表明抗贫血药物 FG4592 在预防与缺血和氧化还原失衡相关的 AKI 向 CKD 转变方面具有治疗作用。
