Erythropoietin prevents vascular inflammation and oxidative stress in subtotal nephrectomized rat aorta beyond haematopoiesis.
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 NO(x) 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.
Toba
Hiroe
H
Department of Clinical Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan. toba@mb.kyoto-phu.ac.jp
Nakashima
Kohei
K
Oshima
Yuko
Y
Kojima
Yushi
Y
Tojo
Chisato
C
Nakano
Arisa
A
Wang
Jiahong
J
Kobara
Miyuki
M
Nakata
Tetsuo
T
D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001013:Aorta, Thoracic / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D003404:Creatinine / Q000097:blood / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology*; D038362:Glycogen Synthase Kinase 3 / Q000096:biosynthesis / Q000378:metabolism; D000071679:Glycogen Synthase Kinase 3 beta; D006400:Hematocrit; D006410:Hematopoiesis / Q000187:drug effects*; D006801:Humans; D006965:Hyperplasia; D008264:Macrophages / Q000187:drug effects; D008297:Male; D019255:NADPH Oxidases / Q000378:metabolism; D009392:Nephrectomy / Q000379:methods; D009569:Nitric Oxide / Q000652:urine; D052250:Nitric Oxide Synthase Type III / Q000096:biosynthesis / Q000378:metabolism; D009599:Nitroprusside / Q000494:pharmacology; D053495:Osteopontin / Q000096:biosynthesis / Q000097:blood; D018384:Oxidative Stress / Q000187:drug effects*; D011507:Proteinuria / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000096:biosynthesis / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins; D013481:Superoxides / Q000378:metabolism; D014657:Vasculitis / Q000378:metabolism / Q000473:pathology / Q000517:prevention & control; D014664:Vasodilation / Q000187:drug effects
D011994:Recombinant Proteins; D053495:Osteopontin; D013481:Superoxides; D004921:Erythropoietin; D009599:Nitroprusside; D009569:Nitric Oxide; D003404:Creatinine; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat; D019255:NADPH Oxidases; C000605506:GSK3B protein, human; D000071679:Glycogen Synthase Kinase 3 beta; C000605508:Gsk3b protein, rat; D051057:Proto-Oncogene Proteins c-akt; D038362:Glycogen Synthase Kinase 3; D000109:Acetylcholine