Erythropoietin prevents vascular inflammation and oxidative stress in subtotal nephrectomized rat aorta beyond haematopoiesis

• Published in: Clinical and experimental pharmacology & physiology Vol. 37; no. 12; pp. 1139 - 1146
• Main Authors: Toba, Hiroe, Nakashima, Kohei, Oshima, Yuko, Kojima, Yushi, Tojo, Chisato, Nakano, Arisa, Wang, Jiahong, Kobara, Miyuki, Nakata, Tetsuo
• Format: Journal Article
• Language: English
• Published: Oxford, UK Blackwell Publishing Ltd 01.12.2010
• Subjects: Acetylcholine - pharmacology; Animals; aorta; Aorta, Thoracic - drug effects; Aorta, Thoracic - metabolism; Aorta, Thoracic - pathology; Blood Pressure - drug effects; Creatinine - blood; Creatinine - metabolism; erythropoietin; Erythropoietin - pharmacology; Glycogen Synthase Kinase 3 - biosynthesis; Glycogen Synthase Kinase 3 - metabolism; Glycogen Synthase Kinase 3 beta; Hematocrit; Hematopoiesis - drug effects; Humans; Hyperplasia; kidney; Macrophages - drug effects; Male; NADPH Oxidases - metabolism; Nephrectomy - methods; Nitric Oxide - urine; nitric oxide synthase; Nitric Oxide Synthase Type III - biosynthesis; Nitric Oxide Synthase Type III - metabolism; Nitroprusside - pharmacology; Osteopontin - biosynthesis; Osteopontin - blood; Oxidative Stress - drug effects; Proteinuria - metabolism; Proto-Oncogene Proteins c-akt - biosynthesis; Proto-Oncogene Proteins c-akt - metabolism; Rats; Rats, Wistar; Recombinant Proteins; Superoxides - metabolism; Vasculitis - metabolism; Vasculitis - pathology; Vasculitis - prevention & control; Vasodilation - drug effects
• ISSN: 0305-1870; 1440-1681
• DOI: 10.1111/j.1440-1681.2010.05445.x

Summary 1. Recombinant human erythropoietin (rHuEPO) has been used for the management of renal anaemia. Recent studies suggest pleiotropic properties of rHuEPO in various tissues. The aim of the present study was to investigate the vasoprotective effects of rHuEPO in renal failure rats. 2. Rats subjected to 5/6 and 17/18 nephrectomy (5/6Nx and 17/18Nx rats, respectively) were treated with rHuEPO (75 U/kg, s.c.) three times a week for 2 weeks. 3. Administration of rHuEPO to 5/6Nx or 17/18Nx rats had no effect on systolic blood pressure or decreased haematocrit. However, rHuEPO treatment normalized proteinuria and creatinine clearance in 5/6Nx, but not in 17/18Nx, rats. 4. Vasodilation in response to acetylcholine in aortic rings was impaired in 5/6Nx and 17/18Nx rats and improved by rHuEPO in both groups. Immunohistochemical analysis revealed that macrophage infiltration into adventitial areas and the expression of osteopontin were enhanced in aortas from 5/6Nx and 17/18Nx rats, but that rHuEPO suppressed these effects. In addition, rHuEPO attenuated medial hyperplasia and NADPH oxidase‐derived superoxide production in 5/6Nx and 17/18Nx rats. 5. Activation of the Akt signalling pathway was evident in rHuEPO‐treated rats as the increased expression of phosphorylated Akt and glycogen synthase kinase‐3β. Treatment with rHuEPO restored the expression of phosphorylated endothelial nitric oxide synthase in the aorta and urinary excretion of NOx in nephrectomized rats. 6. These results suggest that a low dose of rHuEPO results in the normalization of endothelial function, vascular inflammation and oxidative stress in rats with renal ablation beyond haematopoiesis. In addition, these vasoprotective effects are observed even in a state of deteriorating renal dysfunction.