Recombinant human erythropoietin ameliorated endothelial dysfunction and macrophage infiltration by increasing nitric oxide in hypertensive 5/6 nephrectomized rat aorta.
Recombinant human erythropoietin ameliorated endothelial dysfunction and macrophage infiltration by increasing nitric oxide in hypertensive 5/6 nephrectomized rat aorta.
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DOI：
10.1016/j.ejphar.2011.01.043
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发表时间：
2011-04
影响因子：
5
通讯作者：
H. Toba;Masayuki Morishita;C. Tojo;A. Nakano;Yuko Oshima;Yushi Kojima;M. Yoshida;Kohei Nakashima;Jiahong Wang;M. Kobara;T. Nakata
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文献类型：
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作者：
H. Toba;Masayuki Morishita;C. Tojo;A. Nakano;Yuko Oshima;Yushi Kojima;M. Yoshida;Kohei Nakashima;Jiahong Wang;M. Kobara;T. Nakata
重组人促红细胞生成素(RHuEPO)是临床上用于治疗肾性贫血的药物，据报道在多种组织中具有多效性。5/6肾切除高血压大鼠(5/6NX)皮下注射1%氯化钠后，皮下注射rHuEPO(75U/kg)，每3天1次，连续10天，观察其对血管损伤的保护作用。RHuEPO对升高收缩压或降低红细胞压积无影响，但可使尿蛋白和内生肌酐清除率恢复正常。5/6NX组大鼠主动脉环对乙酰胆碱反应的血管扩张功能受损，经rHuEPO治疗后血管扩张功能得到改善。免疫组织化学分析显示，5/6NX大鼠主动脉外膜巨噬细胞浸润和骨桥蛋白表达增强，rHuEPO可抑制其过度表达。RHuEPO还可减轻中层增生。RHuEPO处理的5/6NX大鼠主动脉中磷酸化Akt和GSK-3β表达增加，激活了Akt信号转导通路。重组人促红细胞生成素可恢复大鼠血浆NO_x(NO_2、−+NO_3、−)水平和5/6NX大鼠主动脉内皮型一氧化氮合酶(ENOS)含量。使用eNOS底物L精氨酸治疗，导致血浆NOx水平与rHuEPO治疗相似，导致内皮功能障碍和血管炎症正常化。这些结果表明，小剂量的rHuEPO对高血压肾功能衰竭大鼠具有血管保护作用。
Recombinant human erythropoietin (rHuEPO), used clinically for renal anemia, reportedly exhibits pleiotropic properties in various tissues. To test whether it ameliorates vascular injury, rHuEPO (75U/kg) was administered subcutaneously every 3days for 10days to 5/6 nephrectomized hypertensive rats (5/6Nx) treated with 1% NaCl. rHuEPO had no effect on increased systolic blood pressure or decreased hematocrit values, but normalized levels of proteinuria and creatinine clearance. Vasodilation in response to acetylcholine in the aortic ring was impaired in the 5/6Nx, and improved by treatment with rHuEPO. Immunohistochemical analysis revealed that the infiltration of adventitial areas by macrophages and expression of osteopontin were enhanced in the 5/6Nx aorta and the overexpression was suppressed by rHuEPO. rHuEPO also attenuated medial hyperplasia. Akt signaling was activated by the increased expression of phosphorylated Akt and GSK-3β in aorta from rHuEPO-treated 5/6Nx. rHuEPO restored plasma NOx (NO2−+NO3−) levels and endothelial nitric oxide synthase (eNOS) content in the 5/6Nx aorta. Treatment with an eNOS substrate, l-arginine, which caused a similar increase in plasma NOx levels as the rHuEPO treatment, resulted in a normalization of endothelial dysfunction and vascular inflammation. These results suggest that a low dose of rHuEPO exerted vasoprotective effects in rats with hypertensive renal failure.