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The oral hypoxia-inducible factor prolyl hydroxylase inhibitor enarodustat counteracts alterations in renal energy metabolism in the early stages of diabetic kidney disease.
Kidney International ( IF 14.8 ) Pub Date : 2019-12-25 , DOI: 10.1016/j.kint.2019.12.007 Sho Hasegawa 1 , Tetsuhiro Tanaka 2 , Tomoyuki Saito 3 , Kenji Fukui 4 , Takeshi Wakashima 4 , Etsuo A Susaki 5 , Hiroki R Ueda 6 , Masaomi Nangaku 2
Kidney International ( IF 14.8 ) Pub Date : 2019-12-25 , DOI: 10.1016/j.kint.2019.12.007 Sho Hasegawa 1 , Tetsuhiro Tanaka 2 , Tomoyuki Saito 3 , Kenji Fukui 4 , Takeshi Wakashima 4 , Etsuo A Susaki 5 , Hiroki R Ueda 6 , Masaomi Nangaku 2
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Hypoxia-inducible factor (HIF) prolyl hydroxylase inhibitors, also known as HIF stabilizers, increase endogenous erythropoietin production and serve as novel therapeutic agents against anemia in chronic kidney disease. HIF induces the expression of various genes related to energy metabolism as an adaptive response to hypoxia. However, it remains obscure how the metabolic reprogramming in renal tissue by HIF stabilization affects the pathophysiology of kidney diseases. Previous studies suggest that systemic metabolic disorders such as hyperglycemia and dyslipidemia cause alterations of renal metabolism, leading to renal dysfunction including diabetic kidney disease. Here, we analyze the effects of enarodustat (JTZ-951), an oral HIF stabilizer, on renal energy metabolism in the early stages of diabetic kidney disease, using streptozotocin-induced diabetic rats and alloxan-induced diabetic mice. Transcriptome analysis revealed that enarodustat counteracts the alterations in diabetic renal metabolism. Transcriptome analysis showed that fatty acid and amino acid metabolisms were upregulated in diabetic renal tissue and downregulated by enarodustat, whereas glucose metabolism was upregulated. These symmetric changes were confirmed by metabolome analysis. Whereas glycolysis and tricarboxylic acid cycle metabolites were accumulated and amino acids reduced in renal tissue of diabetic animals, these metabolic disturbances were mitigated by enarodustat. Furthermore, enarodustat increased the glutathione to glutathione disulfide ratio and relieved oxidative stress in renal tissue of diabetic animals. Thus, HIF stabilization counteracts alterations in renal energy metabolism occurring in incipient diabetic kidney disease.
中文翻译：
口服缺氧诱导因子脯氨酰羟化酶抑制剂enarodustat抵消了糖尿病性肾脏疾病早期肾脏能量代谢的改变。
缺氧诱导因子（HIF）脯氨酰羟化酶抑制剂，也称为HIF稳定剂，可增加内源性促红细胞生成素的产生，并作为针对慢性肾脏疾病贫血的新型治疗剂。HIF诱导与能量代谢有关的各种基因的表达，作为对缺氧的适应性反应。然而，仍然不清楚的是，通过HIF稳定作用在肾脏组织中进行的代谢重编程如何影响肾脏疾病的病理生理。先前的研究表明，全身性代谢紊乱，例如高血糖症和血脂异常，会引起肾脏代谢的改变，从而导致包括糖尿病性肾脏疾病在内的肾脏功能障碍。在这里，我们分析了口服HIF稳定剂Enarodustat（JTZ-951）对糖尿病肾病早期阶段肾脏能量代谢的影响，使用链脲佐菌素诱导的糖尿病大鼠和四氧嘧啶诱导的糖尿病小鼠。转录组分析表明，依诺度他可以抵消糖尿病肾代谢的改变。转录组分析表明，糖尿病肾组织中的脂肪酸和氨基酸代谢被上调，而依那度达则被下调，而葡萄糖代谢被上调。这些对称变化通过代谢组学分析得到证实。尽管糖尿病动物的肾脏组织中糖酵解和三羧酸循环代谢物积累，氨基酸减少，但依诺度他可以减轻这些代谢紊乱。此外，enarodustat可增加糖尿病动物肾脏组织中谷胱甘肽与谷胱甘肽二硫化物的比例并缓解氧化应激。因此，
更新日期：2019-12-25
中文翻译：
口服缺氧诱导因子脯氨酰羟化酶抑制剂enarodustat抵消了糖尿病性肾脏疾病早期肾脏能量代谢的改变。
缺氧诱导因子（HIF）脯氨酰羟化酶抑制剂，也称为HIF稳定剂，可增加内源性促红细胞生成素的产生，并作为针对慢性肾脏疾病贫血的新型治疗剂。HIF诱导与能量代谢有关的各种基因的表达，作为对缺氧的适应性反应。然而，仍然不清楚的是，通过HIF稳定作用在肾脏组织中进行的代谢重编程如何影响肾脏疾病的病理生理。先前的研究表明，全身性代谢紊乱，例如高血糖症和血脂异常，会引起肾脏代谢的改变，从而导致包括糖尿病性肾脏疾病在内的肾脏功能障碍。在这里，我们分析了口服HIF稳定剂Enarodustat（JTZ-951）对糖尿病肾病早期阶段肾脏能量代谢的影响，使用链脲佐菌素诱导的糖尿病大鼠和四氧嘧啶诱导的糖尿病小鼠。转录组分析表明，依诺度他可以抵消糖尿病肾代谢的改变。转录组分析表明，糖尿病肾组织中的脂肪酸和氨基酸代谢被上调，而依那度达则被下调，而葡萄糖代谢被上调。这些对称变化通过代谢组学分析得到证实。尽管糖尿病动物的肾脏组织中糖酵解和三羧酸循环代谢物积累，氨基酸减少，但依诺度他可以减轻这些代谢紊乱。此外，enarodustat可增加糖尿病动物肾脏组织中谷胱甘肽与谷胱甘肽二硫化物的比例并缓解氧化应激。因此，
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