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

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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