Division of Nephrology and Endocrinology.
Division of Nephrology and Endocrinology,
J Am Soc Nephrol. 2020 Mar;31(3):560-577. doi: 10.1681/ASN.2019060582. Epub 2020 Jan 29.
Prolyl hydroxylase domain (PHD) inhibitors, which stimulate erythropoietin production through the activation of hypoxia-inducible factor (HIF), are novel therapeutic agents used for treating renal anemia. Several PHD inhibitors, including enarodustat, are currently undergoing phase 2 or phase 3 clinical trials. Because HIF regulates a broad spectrum of genes, PHD inhibitors are expected to have other effects in addition to erythropoiesis, such as protection against metabolic disorders. However, whether such beneficial effects would extend to metabolic disorder-related kidney disease is largely unknown.
We administered enarodustat or vehicle without enarodustat in feed to diabetic black and tan brachyury (BTBR) mice from 4 to 22 weeks of age. To elucidate molecular changes induced by enarodustat, we performed transcriptome analysis of isolated glomeruli and experiments using murine mesangial cells.
Compared with BTBR mice that received only vehicle, BTBR mice treated with enarodustat displayed lower body weight, reduced blood glucose levels with improved insulin sensitivity, lower total cholesterol levels, higher adiponectin levels, and less adipose tissue, as well as a tendency for lower macrophage infiltration. Enarodustat-treated mice also exhibited reduced albuminuria and amelioration of glomerular epithelial and endothelial damage. Transcriptome analysis of isolated glomeruli revealed reduced expression of C-C motif chemokine ligand 2/monocyte chemoattractant protein-1 (CCL2/MCP-1) in enarodustat-treated mice compared with the vehicle-only group, accompanied by reduced glomerular macrophage infiltration. experiments demonstrated that both local HIF-1 activation and restoration of adiponectin by enarodustat contributed to CCL2/MCP-1 reduction in mesangial cells.
These results indicate that the PHD inhibitor enarodustat has potential renoprotective effects in addition to its potential to protect against metabolic disorders.
脯氨酰羟化酶结构域（PHD）抑制剂通过激活低氧诱导因子（HIF）刺激促红细胞生成素的产生，是用于治疗肾性贫血的新型治疗药物。几种 PHD 抑制剂，包括恩曲司他，目前正在进行 2 期或 3 期临床试验。由于 HIF 调节广泛的基因，除了促红细胞生成作用外，PHD 抑制剂预计还具有其他作用，如预防代谢紊乱。然而，这种有益作用是否会扩展到代谢紊乱相关的肾脏疾病尚不清楚。
我们从 4 到 22 周龄时，用含或不含恩曲司他的饲料给糖尿病黑棕褐（BTBR）小鼠喂食。为了阐明恩曲司他诱导的分子变化，我们对分离的肾小球进行了转录组分析，并使用鼠系膜细胞进行了实验。
与仅接受载体的 BTBR 小鼠相比，用恩曲司他治疗的 BTBR 小鼠体重降低，血糖水平降低，胰岛素敏感性提高，总胆固醇水平降低，脂联素水平升高，脂肪组织减少，巨噬细胞浸润减少。恩曲司他治疗的小鼠还表现出蛋白尿减少和肾小球上皮和内皮损伤的改善。分离肾小球的转录组分析显示，与仅用载体组相比，恩曲司他治疗的小鼠 C-C 基序趋化因子配体 2/单核细胞趋化蛋白-1（CCL2/MCP-1）的表达降低，肾小球内巨噬细胞浸润减少。实验表明，恩曲司他既能局部激活 HIF-1，又能恢复脂联素，这两者都有助于系膜细胞中 CCL2/MCP-1 的减少。
这些结果表明，PHD 抑制剂恩曲司他除了具有预防代谢紊乱的作用外，还有潜在的肾保护作用。
