Department of Cardiovascular and Renal Medicine, School of Medicine, Hyogo Medical University, Nishinomiya.
Division of Pharmaceutical Therapeutics, Department of Pharmacy, School of Pharmacy, Hyogo Medical University, Kobe.
J Hypertens. 2024 Mar 1;42(3):497-505. doi: 10.1097/HJH.0000000000003623. Epub 2023 Nov 27.
Although hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors have been developed for the treatment of renal anemia, their effects on cardiac and renal dysfunction remain unknown. We previously reported on Dahl salt-sensitive rats, in a rat model of salt-sensitive hypertension, that exhibited anemia and impaired expression of duodenal iron transporters after the development of hypertensive cardiac and renal dysfunction. Therefore, we investigated the effects of Roxadustat (FG-4592), an HIF-PH inhibitor, on anemia, iron regulation, and cardiac and renal dysfunction in Dahl salt-sensitive rats.
Six-week-old male Dahl salt-sensitive rats were fed a normal or high-salt diet for 8 weeks. A further subset of Dahl salt-sensitive rats, that were fed a high-salt diet, was administered Roxadustat for 8 weeks.
Dahl salt-sensitive rats fed a high-salt diet developed hypertension, cardiac and renal dysfunction, and anemia after 8 weeks of feeding. Roxadustat increased hemoglobin and serum erythropoietin levels in Dahl salt-sensitive rats fed a high-salt diet. With regard to the iron-regulating system, Roxadustat lowered hepatic hepcidin gene expression and increased the gene expression of duodenal iron transporters, such as cytochrome b and divalent metal transporter 1 , in Dahl salt-sensitive rats fed a high-salt diet. Roxadustat did not affect the development of hypertension and cardiac hypertrophy in Dahl salt-sensitive rats with a high-salt diet; however, Roxadustat treatment attenuated renal fibrosis in these rats.
Roxadustat ameliorated anemia with affecting the gene expression of the iron-regulating system, and did not affect cardiac hypertrophy but attenuated renal fibrosis in Dahl salt-sensitive rats fed a high-salt diet.
尽管缺氧诱导因子脯氨酰羟化酶（HIF-PH）抑制剂已被开发用于治疗肾性贫血，但它们对心脏和肾脏功能障碍的影响仍不清楚。我们之前曾报道过盐敏感型 Dahl 大鼠，在盐敏感型高血压大鼠模型中，高血压性心脏和肾脏功能障碍发展后，会出现贫血和十二指肠铁转运蛋白表达受损。因此，我们研究了 HIF-PH 抑制剂罗沙司他（FG-4592）对盐敏感型 Dahl 大鼠贫血、铁调节以及心脏和肾脏功能障碍的影响。
将 6 周龄雄性盐敏感型 Dahl 大鼠分别用正常或高盐饮食喂养 8 周。其中一部分盐敏感型 Dahl 大鼠用高盐饮食喂养，并给予罗沙司他 8 周。
用高盐饮食喂养 8 周后，盐敏感型 Dahl 大鼠出现高血压、心脏和肾脏功能障碍以及贫血。罗沙司他增加了高盐饮食喂养的盐敏感型 Dahl 大鼠的血红蛋白和血清促红细胞生成素水平。在铁调节系统方面，罗沙司他降低了肝组织中hepcidin 基因的表达，并增加了高盐饮食喂养的盐敏感型 Dahl 大鼠十二指肠铁转运蛋白（如细胞色素 b 和二价金属转运蛋白 1）的基因表达。罗沙司他对高盐饮食喂养的盐敏感型 Dahl 大鼠高血压和心脏肥大的发展没有影响；然而，罗沙司他治疗减轻了这些大鼠的肾纤维化。
罗沙司他改善了贫血，同时影响了铁调节系统的基因表达，对心脏肥大没有影响，但减轻了高盐饮食喂养的盐敏感型 Dahl 大鼠的肾纤维化。
