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Roxadustat prevents Ang II hypertension by targeting angiotensin receptors and eNOS
Jing Yu, … , Aihua Zhang, Zhanjun Jia
Jing Yu, … , Aihua Zhang, Zhanjun Jia
Published August 17, 2021
Citation Information: JCI Insight. 2021;6(18):e133690. https://doi.org/10.1172/jci.insight.133690.
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Research Article Nephrology Vascular biology

Roxadustat prevents Ang II hypertension by targeting angiotensin receptors and eNOS

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Abstract

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.

Authors

Jing Yu, Shuqin Wang, Wei Shi, Wei Zhou, Yujia Niu, Songming Huang, Yue Zhang, Aihua Zhang, Zhanjun Jia

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Figure 4

Effects of FG-4592 on urine volume and urinary electrolyte output in Ang II–treated mice.

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Effects of FG-4592 on urine volume and urinary electrolyte output in Ang...
(A) Urine volume. (B) Urinary osmolality. (C) Urinary Na+ excretion. (D) Urinary K+ excretion. (E) Urinary Cl– excretion. Data are presented as mean ± SD (n = 10 per group). Significance values were determined by 1-way ANOVA. Newman-Keuls multiple-comparison test was used for multiple comparisons. Ctrl , DMSO in saline. *P < 0.05, **P < 0.01.

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