Investigation into the tissue-protective effects of erythropoietin against cardio-renal syndrome

促红细胞生成素对心肾综合征的组织保护作用的研究

• 批准号: 23790608
• 负责人: TOBA Hiroe
• 金额: $ 2万
• 依托单位: Kyoto Pharmaceutical University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Young Scientists (B)
• 财政年份: 2011
• 资助国家: 日本
• 起止时间: 2011 至 2012
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-23790608/
• 关键词: 臨床薬理学; 心腎連関

CKD was induced by five-sixths or seventeen-eighteenths nephrectomy. Proteinuria and CCr were aggravated and plasma ADMA level was increased in accordance with the degree of nephrectomy. Endothelial-dependent vasodilation was blunted and macrophage infiltration, osteopontin expression, NADPH oxidase-derived superoxide production and ACE activity were increased in nephrectomized rat aortas. These changes are correlated with the degree of renal dysfunction. ADMA enhanced the NADPH oxidase activity in endothelial cells, which was inhibited by cotreatment with ACE inhibitor, captopril. ADMA induced vascular injury not only by inhibiting NOS but also by inducing oxidative stress via ACE activation in CKD. On the other hand, low dose of erythropoietin inhibits endothelial dysfunction and inflammation in CKD and diabetic rat aorta beyond hematopoiesis. Erythropoietin reversed the levels of phospho-Akt and eNOS protein and plasma NOx, which were reduced in 5/6Nx. Furthermore, erythropoietin wa … More s administered to NO synthase inhibitor (L-NAME, 0.7 mg/ml)-treated rats. Erythropoietin improved endothelium-dependent vasodilatation. Macrophage infiltration in L-NAME-treated rats was reduced by erythropoietin. Erythropoietin enhanced the levels of phospho-Akt, HO-1 and Cu/Zn-SOD protein. The increased NADPH oxidase-derived superoxide production in L-NAME-treated rat was suppressed by erythropoietin. Erythropoietin also induced SOCS1 overexpression. Cotreatment with STAT5 inhibitor cancelled erythropoietin-induced suppression in NADPH oxidase-derived superoxide production in angiotensinII-treated endothelial cells. In conclusion, erythropoietin exhibited vasoprotective effects via NO production through Akt pathway. In addition, erythropoietin improved vascular injury in L-NAME-treated rats by antioxidativeproperties. SOCS-1 overexpression would play an important role in suppressing NADPH oxidase activation as its mechanisms. In conclusion, erythropoietin exerts vasoprotective effects in CKD rats beyond hematopoiesis. Less

CKD是由5/6或17/18肾切除诱发的。随着肾切除程度的加重，蛋白尿和CCr加重，血浆ADMA水平升高。在肾切除大鼠动脉中，内皮依赖性血管舒张减弱，巨噬细胞浸润，骨桥蛋白表达，NADPH氧化酶衍生的超氧化物产生和ACE活性增加。这些变化与肾功能不全的程度有关。ADMA可增强内皮细胞NADPH氧化酶活性，而ACE抑制剂Captopril可抑制ADMA的作用。ADMA不仅通过抑制NOS诱导血管损伤，还通过ACE激活诱导氧化应激。另一方面，低剂量的促红细胞生成素抑制CKD和糖尿病大鼠主动脉中的内皮功能障碍和炎症，而不仅仅是造血。促红细胞生成素逆转了5/6 Nx中磷酸化Akt和eNOS蛋白以及血浆NOx的水平。此外，促红细胞生成素是一种 ...更多信息 NO合成酶抑制剂（L-NAME，0.7mg/ml）处理的大鼠。促红细胞生成素改善内皮依赖性血管舒张。促红细胞生成素可减少L-NAME处理大鼠的巨噬细胞浸润。促红细胞生成素可提高磷酸化Akt、HO-1和Cu/Zn-SOD蛋白水平。促红细胞生成素抑制了L-NAME处理大鼠中NADPH氧化酶衍生的超氧化物产生的增加。促红细胞生成素也诱导SOCS 1过表达。STAT 5抑制剂的共同治疗取消促红细胞生成素诱导的抑制NADPH氧化酶衍生的超氧化物生成血管紧张素II处理的内皮细胞。总之，促红细胞生成素通过Akt途径产生NO发挥血管保护作用。此外，促红细胞生成素通过抗氧化作用改善L-NAME治疗大鼠的血管损伤。SOCS-1过表达可能通过抑制NADPH氧化酶活性发挥重要作用。总之，促红细胞生成素在CKD大鼠中发挥的血管保护作用超出了造血作用。少

项目成果

Vascular dysfunction and remodeling ocurred in accordance with renal impairment in nephrectomized rats.

肾切除大鼠中血管功能障碍和重塑的发生与肾损伤一致。

• 发表时间: 2011
• 作者: Hiroe Toba;Shoko Murata;Yuko Oshima;Yushi Kojima;Kohei Nakashima;Kazuki Noda;Jiahong Wang;Miyuki Kobara;Tetsuo Nakata
• 通讯作者: Tetsuo Nakata

Endothelial dysfunction, macrophage infiltration and NADPH oxidase-dependent superoxide production were attenuated by erythropoietin in streptozotocin-induced diabetic rat aorta.

在链脲佐菌素诱导的糖尿病大鼠主动脉中，促红细胞生成素可减弱内皮功能障碍、巨噬细胞浸润和 NADPH 氧化酶依赖性超氧化物的产生。

• DOI: 10.1159/000343963
• 发表时间: 2013
• 期刊: Pharmacology
• 影响因子: 3.1
• 作者: Wang J;Toba H;Morita Y;Nakashima K;Noda K;Tian W;Kobara M;Nakata T
• 通讯作者: Nakata T

Erythropoietin attenuated vascular dysfunction and inflammation by inhibiting NADPH oxidase-derived superoxide production in nitric oxide synthase-inhibited hypertensive rat aorta

• DOI: 10.1016/j.ejphar.2012.07.018
• 发表时间: 2012-09-15
• 期刊: EUROPEAN JOURNAL OF PHARMACOLOGY
• 影响因子: 5
• 作者: Toba, Hiroe;Kojima, Yushi;Nakata, Tetsuo
• 通讯作者: Nakata, Tetsuo

Recombinant human erythropoietin ameliorated endothelial dysfunction and macrophage infiltration by increasing nitric oxide in hypertensive 5/6 nephrectomized rat aorta.

• DOI: 10.1016/j.ejphar.2011.01.043
• 发表时间: 2011-04
• 期刊: European journal of pharmacology
• 影响因子: 5
• 作者: H. Toba;Masayuki Morishita;C. Tojo;A. Nakano;Yuko Oshima;Yushi Kojima;M. Yoshida;Kohei Nakashima;Jiahong Wang;M. Kobara;T. Nakata

Low dose oferythropoietin improved endothelial dysfunction and inflammation in 5/6 nephrectomized rat aorta beyond hematopoiesis

低剂量促红细胞生成素改善5/6肾切除大鼠主动脉造血以外的内皮功能障碍和炎症

• 发表时间: 2011
• 作者: Hiroe Toba;Kohei Nakashima;Yuko Oshima,Yushi Kojima;Chisato Tojo;Jiahong Wang;Miyuki Kobara;and Tetsuo Nakata
• 通讯作者: and Tetsuo Nakata