title: Epoetin beta pegol prevents endothelial dysfunction as evaluated by flow-mediated dilation in chronic kidney disease rats.
abstract: Chronic kidney disease (CKD) patients have a poor prognosis due to cardiovascular disease. Anemia and endothelial dysfunction are important risk factors for cardiovascular events in CKD patients, and treatment with erythropoiesis-stimulating agent (ESA) has been reported to improve the quality of life in CKD patients. In this study, we evaluated the effect of anemia correcting dose of epoetin beta pegol (continuous erythropoietin receptor activator; C.E.R.A.) on endothelial function in 5/6 nephrectomized rats (Nx rats). C.E.R.A. was subcutaneously administered once a fortnight, 5 times in total, from 1 week after nephrectomy. Twenty-four hours after last administration, endothelial function was evaluated by measuring flow-mediated dilation (FMD) in the femoral arteries of anesthetized Nx rats by ultrasound system. Femoral arteries were harvested for western blot analysis. C.E.R.A. significantly increased FMD of Nx rats. Endothelium-independent vasodilation induced by nitroglycerin injection was not influenced by C.E.R.A treatment. Nox4 expression and nitrotyrosine accumulation were significantly decreased, and phosphorylation of eNOS was significantly enhanced in the femoral arteries of C.E.R.A.-treated rats. C.E.R.A. normalized hemoglobin levels but did not affect body weight, systolic blood pressure, heart rate, urinary protein excretion and plasma creatinine. These results indicate that C.E.R.A. prevented endothelial dysfunction in Nx rats, possibly through reduction of local oxidative stress and enhancement of eNOS phosphorylation in the arteries. This study provides the first evidence that C.E.R.A. prevented endothelial dysfunction in CKD model rats under conditions of amelioration of anemia.
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Kenichi
authors.initials: K
authors.lastname: Serizawa
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yogo
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Tashiro
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Ken
authors.initials: K
authors.lastname: Aizawa
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Kawasaki
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan.
authors.forename: Michinori
authors.initials: M
authors.lastname: Hirata
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd., 1-135 Komakado, Gotemba, Shizuoka 412-8513, Japan. Electronic address: endokui@chugai-pharm.co.jp.
authors.forename: Koichi
authors.initials: K
authors.lastname: Endo
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D001835:Body Weight / Q000187:drug effects; D003404:Creatinine / Q000097:blood; D004195:Disease Models, Animal; D004730:Endothelium, Vascular / Q000187:drug effects*; D004921:Erythropoietin / Q000494:pharmacology*; D005263:Femoral Artery / Q000000981:diagnostic imaging / Q000187:drug effects / Q000378:metabolism; D006339:Heart Rate / Q000187:drug effects; D006454:Hemoglobins / Q000378:metabolism; D007677:Kidney Function Tests; D008297:Male; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases / Q000096:biosynthesis; D009392:Nephrectomy; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism; D005996:Nitroglycerin / Q000494:pharmacology; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011507:Proteinuria / Q000652:urine; D051381:Rats; D051436:Renal Insufficiency, Chronic / Q000097:blood / Q000378:metabolism* / Q000652:urine; D014443:Tyrosine / Q000031:analogs & derivatives / Q000378:metabolism; D014463:Ultrasonography; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D006454:Hemoglobins; C508420:continuous erythropoietin receptor activator; D004921:Erythropoietin; C002744:3-nitrotyrosine; D011092:Polyethylene Glycols; D014443:Tyrosine; D003404:Creatinine; D052250:Nitric Oxide Synthase Type III; D000074663:NADPH Oxidase 4; D019255:NADPH Oxidases; C498911:Nox4 protein, rat; D005996:Nitroglycerin
keywords: Chronic kidney disease; Continuous erythropoietin receptor activator; Endothelial dysfunction; Epoetin beta pegol; Erythropoietin; Flow-mediated dilation