Erythropoietin Synthesis in Renal Myofibroblasts Is Restored by Activation of Hypoxia Signaling
Erythropoietin Synthesis in Renal Myofibroblasts Is Restored by Activation of Hypoxia Signaling
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DOI：
10.1681/asn.2014121184
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发表时间：
2016-02-01
影响因子：
13.6
通讯作者：
Suzuki, Norio
中科院分区：
文献类型：
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作者：
Souma, Tomokazu;Nezu, Masahiro;Suzuki, Norio
促红细胞生成素 (Epo) 由肾促红细胞生成细胞 (REP) 以缺氧诱导的方式产生。 REP 转化为肌成纤维细胞以及同时丧失 EPO 生成能力是肾纤维化和贫血的主要原因。然而，这些转化的肌成纤维细胞的缺氧反应仍不清楚。在这里，我们使用互补的体内转基因和实时成像方法来更好地了解缺氧信号在 Epo 产生中的重要性。对表达来自修饰的 Epo 基因位点的绿色荧光蛋白的转基因小鼠中的 REP 进行实时成像显示，健康的 REP 通过包裹毛细血管的过程与内皮紧密相关。然而，这种关联在肾损伤诱导的炎症状态中受到阻碍，先前显示这些炎症与向肌成纤维细胞转化的肾促红细胞生成素生成细胞（MF-REP）的转变相关。此外，通过在 Epo 生成细胞中选择性地基因灭活 HIF-脯氨酰羟化酶（PHD1、PHD2 和 PHD3）来激活缺氧诱导因子 (HIF)，从而重新激活 MF-REP 中的 Epo 生成。 REP 中 PHD2 的缺失恢复了受损肾脏中 Epo 基因的表达，但导致红细胞增多症。值得注意的是，PHD1 和 PHD3 的联合缺失可以防止 Epo 表达的丧失，而不会引起红细胞增多症。具有 PHD 缺陷的 REP 的小鼠也表现出对肾脏中 LPS 诱导的 Epo 抑制的抵抗力，这表明增强的 HIF 信号传导可以平衡 Epo 产生调节中的炎症刺激。因此，通过重新激活 MF-REP 中的 Epo 合成，增强 HIF 信号传导可能是治疗肾性贫血的一种有吸引力的治疗策略。
Erythropoietin (Epo) is produced by renal Epo-producing cells (REPs) in a hypoxia-inducible manner. The conversion of REPs into myofibroblasts and coincident loss of Epo-producing ability are the major cause of renal fibrosis and anemia. However,, the hypoxic response of these transformed myofibroblasts remains unclear. Here, we used complementary in vivo transgenic and live imaging approaches to better understand the importance of hypoxia signaling in Epo production. Live imaging of REPs in transgenic mice expressing green fluorescent protein from a modified Epo-gene locus revealed that healthy REPs tightly associated with endothelium by wrapping processes around capillaries. However, this association was hampered in states of renal injury-induced inflammation previously shown to correlate with the transition to myofibroblast-transformed renal Epo-producing cells (MF-REPs). Furthermore, activation of hypoxia-inducible factors (HIFs) by genetic inactivation of HIF-prolyl hydroxylases (PHD1, PHD2, and PHD3) selectively in Epo-producing cells reactivated Epo production in MF-REPs. Loss of PHD2 in REPs restored Epo-gene expression in injured kidneys but caused polycythemia. Notably, combined deletions of PHD1 and PHD3 prevented loss of Epo expression without provoking polycythemia. Mice with PHD-deficient REPs also showed resistance to LPS-induced Epo repression in kidneys, suggesting that augmented HIF signaling counterbalances inflammatory stimuli in regulation of Epo production. Thus, augmentation of HIF signaling may be an attractive therapeutic strategy for treating renal anemia by reactivating Epo synthesis in MF-REPs.