Asymmetric Dimethylarginine Contributes to the Impaired Response to Erythropoietin in CKD-Anemia.
Asymmetric Dimethylarginine Contributes to the Impaired Response to Erythropoietin in CKD-Anemia.
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DOI：
10.1681/asn.2016111184
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发表时间：
2017-09
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通讯作者：
M. Yokoro;Yosuke Nakayama;S. Yamagishi;Ryotaro Ando;M. Sugiyama;S. Ito;J. Yano;K. Taguchi;Y. Kaida;D. Saigusa;M. Kimoto;T. Abe;S. Ueda;K. Fukami
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作者：
M. Yokoro;Yosuke Nakayama;S. Yamagishi;Ryotaro Ando;M. Sugiyama;S. Ito;J. Yano;K. Taguchi;Y. Kaida;D. Saigusa;M. Kimoto;T. Abe;S. Ueda;K. Fukami
促红细胞生成素抵抗性贫血与 ESRD 患者的不良心血管事件相关，但其潜在机制仍不清楚。在这里，我们评估了内源性一氧化氮合酶抑制剂不对称二甲基精氨酸 (ADMA) 的作用。在 54 名晚期 CKD 患者中，红细胞而非血浆 ADMA 水平与低血红蛋白值独立相关，尽管两种类型的 ADMA 水平均高于健康志愿者。此外，在接受每周注射剂量的红细胞生成刺激剂（针对血红蛋白水平和体重进行标准化）的患者中，红细胞ADMA水平与红细胞生成素抵抗指数相关，而在未接受红细胞生成刺激剂的患者中，红细胞ADMA水平与红细胞生成素需求指数（血浆红细胞生成素单位除以血红蛋白值）相关。与假手术对照组相比，接受 5/6 肾次全切除术 (Nx)（一种晚期 CKD 残肾模型）的野生型小鼠的血红蛋白、血细胞比容和平均红细胞体积值降低，但红细胞和血浆 ADMA 以及血浆促红细胞生成素水平升高。相比之下，有效代谢 ADMA 的二甲基精氨酸二甲氨基水解酶-1 转基因 (DDAH-1 Tg) 小鼠在 5/6 Nx 后除促红细胞生成素外的所有值都有显着改善。此外，野生型 Nx 小鼠（而非 DDAH-1 Tg Nx 小鼠）的脾脏促红细胞生成素受体和红细胞铁酮基因表达降低，红细胞生成素受体和红细胞铁酮调节铁代谢以响应促红细胞生成素。这项研究表明，红细胞 ADMA 积累通过抑制促红细胞生成素受体表达，导致透析前患者和晚期 CKD 小鼠对促红细胞生成素的反应受损。
Erythropoietin-resistant anemia is associated with adverse cardiovascular events in patients with ESRD, but the underlying mechanism remains unclear. Here, we evaluated the role of the endogenous nitric oxide synthase inhibitor asymmetric dimethylarginine (ADMA). In 54 patients with advanced CKD, erythrocyte but not plasma ADMA levels independently associated with low hemoglobin values, although levels of both types of ADMA were elevated compared with those in healthy volunteers. Furthermore, erythrocyte ADMA level associated with the erythropoietin resistance index in patients receiving a weekly injected dose of erythropoiesis-stimulating agents standardized for hemoglobin levels and body weight, whereas it correlated with the erythropoietin demand index (plasma erythropoietin units divided by the hemoglobin value) in patients not receiving erythropoiesis-stimulating agents. Compared with sham-operated controls, wild-type mice with 5/6 subtotal nephrectomy (Nx), a remnant kidney model with advanced CKD, had decreased hemoglobin, hematocrit, and mean corpuscular volume values but increased erythrocyte and plasma ADMA and plasma erythropoietin levels. In comparison, dimethylarginine dimethlaminohydrolase-1 transgenic (DDAH-1 Tg) mice, which efficiently metabolized ADMA, had significant improvements in all of the values except those for erythropoietin after 5/6 Nx. Additionally, wild-type Nx mice, but not DDAH-1 Tg Nx mice, had reduced splenic gene expression of erythropoietin receptor and erythroferrone, which regulates iron metabolism in response to erythropoietin. This study suggests that erythrocyte ADMA accumulation contributes to impaired response to erythropoietin in predialysis patients and advanced CKD mice via suppression of erythropoietin receptor expression.