BACKGROUND 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. METHODS We administered enarodustat or vehicle without enarodustat in feed to diabetic black and tan brachyury (BTBR) ob/ob mice from 4 to 22 weeks of age. To elucidate molecular changes induced by enarodustat, we performed transcriptome analysis of isolated glomeruli and in vitro experiments using murine mesangial cells. RESULTS Compared with BTBR ob/ob mice that received only vehicle, BTBR ob/ob 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. In vitro experiments demonstrated that both local HIF-1 activation and restoration of adiponectin by enarodustat contributed to CCL2/MCP-1 reduction in mesangial cells. CONCLUSIONS These results indicate that the PHD inhibitor enarodustat has potential renoprotective effects in addition to its potential to protect against metabolic disorders.

中文翻译：

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脯氨酰羟化酶域抑制剂可预防肥胖的2型糖尿病小鼠的代谢紊乱和相关的肾脏疾病。

背景技术脯氨酰羟化酶结构域（PHD）抑制剂通过激活缺氧诱导因子（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剂。几种PHD抑制剂，包括Enarodustat，目前正在进行2期或3期临床试验。因为HIF调节广泛的基因，所以PHD抑制剂除了促红细胞生成作用外，还有望发挥其他作用，例如防止代谢紊乱。但是，这种有益效果是否会扩展到与代谢紊乱有关的肾脏疾病尚不清楚。方法我们向4至22周龄的糖尿病黑和棕褐色短臂猿（BTBR）ob / ob小鼠的饲料中施用了enarodustat或不含enarodustat的赋形剂。为了阐明依那度达引起的分子变化，我们使用鼠系膜细胞进行了分离的肾小球的转录组分析和体外实验。结果与仅接受赋形剂的BTBR ob / ob小鼠相比，用enarodustat治疗的BTBR ob / ob小鼠表现出较低的体重，降低的血糖水平，改善的胰岛素敏感性，较低的总胆固醇水平，较高的脂联素水平和较少的脂肪组织，以及巨噬细胞浸润的趋势。接受Enarodustat治疗的小鼠还表现出降低的蛋白尿以及肾小球上皮和内皮损伤的改善。分离的肾小球的转录组分析显示，与仅用赋形剂的组相比，在enarodustat治疗的小鼠中CC基序趋化因子配体2 /单核细胞趋化蛋白1（CCL2 / MCP-1）的表达减少，同时肾小球巨噬细胞浸润减少。体外实验表明，enarodustat对局部HIF-1的激活和脂联素的恢复均有助于肾小球膜细胞CCL2 / MCP-1的减少。结论这些结果表明，PHD抑制剂依那度达除了具有预防代谢异常的潜力外，还具有潜在的肾脏保护作用。