Nanjing Key Laboratory of Pediatrics and.
Department of Nephrology, Children's Hospital of Nanjing Medical University, Nanjing, China.
JCI Insight. 2021 Sep 22;6(18):e133690. doi: 10.1172/jci.insight.133690.
The prevalence of hypertension is increasing globally, while strategies for prevention and treatment of hypertension remain limited. FG-4592 (Roxadustat) is a potentially novel, orally active small-molecule hypoxia-inducible factor (HIF) stabilizer and is being used clinically to treat chronic kidney disease (CKD) anemia. In the present study, we evaluate the effects of FG-4592 on hypertension. In an angiotensin II (Ang II) hypertension model, FG-4592 abolished hypertensive responses; prevented vascular thickening, cardiac hypertrophy, and kidney injury; downregulated AGTR1 expression; and enhanced AGTR2, endothelial NO synthase (eNOS), and HIF1α protein levels in the aortas of mice. Additionally, the levels of thiobarbituric acid reactive substances (TBARs) in blood and urine were diminished by FG-4592 treatment. In vascular smooth muscle cells, FG-4592 treatment reduced angiotensin receptor type 1 (AGTR1) and increased AGTR2 levels, while preventing Ang II-induced oxidative stress. In vascular endothelial cells, FG-4592 upregulated total and phosphorylated eNOS. Moreover, FG-4592 treatment was hypotensive in L-NAME-induced hypertension. In summary, FG-4592 treatment remarkably ameliorated hypertension and organ injury, possibly through stabilizing HIF1α and subsequently targeting eNOS, AGTR1, AGTR2, and oxidative stress. Therefore, in addition to its role in treating CKD anemia, FG-4592 could be explored as a treatment for hypertension associated with high renin angiotensin system (RAS) activity or eNOS defects.
高血压的患病率在全球范围内不断增加，而高血压的预防和治疗策略仍然有限。FG-4592（罗沙司他）是一种潜在的新型、口服活性的低氧诱导因子（HIF）稳定剂，目前正在临床上用于治疗慢性肾脏病（CKD）贫血。在本研究中，我们评估了 FG-4592 对高血压的影响。在血管紧张素 II（Ang II）高血压模型中，FG-4592 消除了高血压反应；预防了血管增厚、心脏肥大和肾脏损伤；下调了血管紧张素受体 1（AGTR1）的表达；并增强了主动脉中的 AGTR2、内皮型一氧化氮合酶（eNOS）和 HIF1α 蛋白水平。此外，FG-4592 治疗还降低了血液和尿液中丙二醛（TBARs）的水平。在血管平滑肌细胞中，FG-4592 治疗降低了血管紧张素受体 1（AGTR1）的水平，增加了 AGTR2 的水平，同时预防了 Ang II 诱导的氧化应激。在血管内皮细胞中，FG-4592 上调了总蛋白和磷酸化型 eNOS。此外，FG-4592 治疗在 L-NAME 诱导的高血压中具有降压作用。总之，FG-4592 治疗显著改善了高血压和器官损伤，这可能是通过稳定 HIF1α，从而靶向 eNOS、AGTR1、AGTR2 和氧化应激。因此，除了在治疗 CKD 贫血中的作用外，FG-4592 还可以被探索用于治疗与高肾素血管紧张素系统（RAS）活性或 eNOS 缺陷相关的高血压。
