Therapeutic Potential of the Prolyl Hydroxylase Inhibitor Roxadustat in a Mouse Hindlimb Lymphedema Model
Therapeutic Potential of the Prolyl Hydroxylase Inhibitor Roxadustat in a Mouse Hindlimb Lymphedema Model
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DOI：
10.1089/lrb.2022.0071
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发表时间：
2023-03-07
影响因子：
1.4
通讯作者：
Maeda，Taku
中科院分区：
文献类型：
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作者：
Hoshino，Yoshitada;Osawa，Masayuki;Maeda，Taku
背景：淋巴水肿是一种难治性疾病，目前尚无有效的治疗方法。保守治疗是主要的，并且强烈需要新的药物治疗选择。本研究的目的是探讨roxadustat，脯氨酰-4-羟化酶抑制剂，对淋巴管生成的影响和其治疗效果在无辐射小鼠后肢水肿mechanism.Methods和结果：雄性C57 BL/6 N小鼠（8-10周龄）用于水肿模型。将小鼠随机分配到接受roxadustat的实验组或对照组。术后28天，通过荧光淋巴造影术评价后肢的周长比，并比较后肢的淋巴流量。roxadustat组显示后肢周长和淋巴流停滞的早期改善。与对照组相比，罗沙杜司他组术后第7天的淋巴管数量和面积分别显著增大和减小。与对照组相比，roxadustat组术后第7天的皮肤厚度和巨噬细胞浸润显著减少。术后第4天，与对照组相比，roxadustat组中缺氧诱导因子-1 α（Hif-1α）、血管内皮生长因子受体-3（VEGFR-3）、血管内皮生长因子-C（VEGF-C）和Prospero同源框1（Prox 1）的相对mRNA表达显著升高。Roxadustat通过激活HIF-1α，VEGF-C，VEGFR-3和Prox 1，表明roxadustat作为治疗水肿的一种选择的潜力。
Background:Lymphedema is an intractable disease with no curative treatment available. Conservative treatment is the mainstay, and new drug treatment options are strongly needed. The purpose of this study was to investigate the effect of roxadustat, a prolyl-4-hydroxylase inhibitor, on lymphangiogenesis and its therapeutic effect on lymphedema in a radiation-free mouse hindlimb lymphedema model.Methods and Results:Male C57BL/6N mice (8–10 weeks old) were used for the lymphedema model. Mice were randomized to an experimental group receiving roxadustat or a control group. The circumferential ratio of the hindlimbs was evaluated, and lymphatic flow of the hindlimbs was compared by fluorescent lymphography up to 28 days postoperatively. The roxadustat group showed an early improvement in hindlimb circumference and stasis of lymphatic flow. The number and area of lymphatic vessels on postoperative day 7 were significantly larger and smaller, respectively, in the roxadustat group compared with the control group. Skin thickness and macrophage infiltration on postoperative day 7 were significantly reduced in the roxadustat group compared with the control group. The relative mRNA expression of hypoxia-inducible factor-1α (Hif-1α), vascular endothelial growth factor receptor-3 (VEGFR-3), vascular endothelial growth factor-C (VEGF-C), and Prospero homeobox 1 (Prox1) on postoperative day 4 was significantly higher in the roxadustat group compared with the control group.Conclusions:Roxadustat demonstrated a therapeutic effect in a murine model of hindlimb lymphedema through promotion of lymphangiogenesis through the activation of HIF-1α, VEGF-C, VEGFR-3, and Prox1, suggesting the potential of roxadustat as a therapeutic option in lymphedema.