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

第六次或第十七次肾切除术引起CKD。蛋白尿、CCr加重，血浆ADMA水平随切除程度升高。内皮依赖性血管舒张功能减弱，巨噬细胞浸润、骨桥蛋白表达、NADPH氧化酶衍生的超氧化物生成和ACE活性升高。这些变化与肾功能不全程度有关。ADMA可增强内皮细胞NADPH氧化酶活性，而与ACE抑制剂卡托普利共处理可抑制该活性。ADMA不仅通过抑制NOS，还通过激活ACE诱导氧化应激，诱导CKD血管损伤。另一方面，低剂量促红细胞生成素对CKD和糖尿病大鼠主动脉内皮功能障碍和炎症的抑制作用超过造血功能。促红细胞生成素逆转了5/6Nx中磷酸化akt和eNOS蛋白水平以及血浆NOx水平。一氧化氮合酶抑制剂（L-NAME, 0.7 mg/ml）对大鼠的促红细胞生成素治疗效果较好。促红细胞生成素改善内皮依赖性血管舒张。促红细胞生成素可降低l - name处理大鼠的巨噬细胞浸润。促红细胞生成素提高磷酸化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SOCS1过表达。在血管紧张素ii处理的内皮细胞中，与STAT5抑制剂共同治疗可消除促红细胞生成素诱导的NADPH氧化酶衍生的超氧化物产生的抑制。综上所述，促红细胞生成素通过Akt通路产生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处理大鼠的血管损伤。SOCS-1过表达可能在抑制NADPH氧化酶激活中发挥重要作用。综上所述，促红细胞生成素对CKD大鼠的血管保护作用超越了造血功能。少

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