title: Recombinant human erythropoietin ameliorated endothelial dysfunction and macrophage infiltration by increasing nitric oxide in hypertensive 5/6 nephrectomized rat aorta.
abstract: 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 (NO(2)(-)+NO(3)(-)) 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.
authors.affiliation: Department of Clinical Pharmacology, Division of Pathological Sciences, Kyoto Pharmaceutical University, Kyoto, Japan. toba@mb.kyoto-phu.ac.jp
authors.forename: Hiroe
authors.initials: H
authors.lastname: Toba
authors.forename: Masayuki
authors.initials: M
authors.lastname: Morishita
authors.forename: Chisato
authors.initials: C
authors.lastname: Tojo
authors.forename: Arisa
authors.initials: A
authors.lastname: Nakano
authors.forename: Yuko
authors.initials: Y
authors.lastname: Oshima
authors.forename: Yushi
authors.initials: Y
authors.lastname: Kojima
authors.forename: Mamiko
authors.initials: M
authors.lastname: Yoshida
authors.forename: Kohei
authors.initials: K
authors.lastname: Nakashima
authors.forename: Jiahong
authors.initials: J
authors.lastname: Wang
authors.forename: Miyuki
authors.initials: M
authors.lastname: Kobara
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Nakata
mesh_terms: D000109:Acetylcholine / Q000494:pharmacology; D000818:Animals; D001011:Aorta / Q000187:drug effects* / Q000293:injuries / Q000378:metabolism / Q000503:physiopathology; D001013:Aorta, Thoracic / Q000187:drug effects / Q000473:pathology; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003238:Connective Tissue / Q000187:drug effects / Q000276:immunology; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000378:metabolism; D004921:Erythropoietin / Q000494:pharmacology*; D015971:Gene Expression Regulation, Enzymologic / Q000187:drug effects; D006400:Hematocrit; D006410:Hematopoiesis / Q000187:drug effects; D006801:Humans; D006973:Hypertension / Q000097:blood / Q000276:immunology / Q000378:metabolism / Q000503:physiopathology*; D008264:Macrophages / Q000187:drug effects* / Q000276:immunology; D008297:Male; D009392:Nephrectomy; D009569:Nitric Oxide / Q000378:metabolism*; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D009585:Nitrogen Dioxide / Q000097:blood; D009589:Nitrogen Oxides / Q000097:blood; D009599:Nitroprusside / Q000494:pharmacology; D053495:Osteopontin / Q000378:metabolism; D010750:Phosphoproteins / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D011994:Recombinant Proteins / Q000494:pharmacology*
chemical_list: D009589:Nitrogen Oxides; D010750:Phosphoproteins; D011994:Recombinant Proteins; D053495:Osteopontin; D004921:Erythropoietin; D009599:Nitroprusside; C031701:nitrogen trioxide; D009569:Nitric Oxide; D052250:Nitric Oxide Synthase Type III; D000109:Acetylcholine; D009585:Nitrogen Dioxide