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: Kenichi Serizawa, Kenji Yogo, Yoshihito Tashiro, Ken Aizawa, Ryohei Kawasaki, Michinori Hirata, Koichi Endo
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 767 Pg. 10-6 (Nov 15 2015) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 26432688 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier B.V. All rights reserved.

Chemical References

• Hemoglobins
• continuous erythropoietin receptor activator
• Erythropoietin
• 3-nitrotyrosine
• Polyethylene Glycols
• Tyrosine
• Creatinine
• Nitric Oxide Synthase Type III
• NADPH Oxidase 4
• NADPH Oxidases
• Nox4 protein, rat
• Nitroglycerin

Topics

• Animals
• Blood Pressure (drug effects)
• Body Weight (drug effects)
• Creatinine (blood)
• Disease Models, Animal
• Endothelium, Vascular (drug effects)
• Erythropoietin (pharmacology)
• Femoral Artery (diagnostic imaging, drug effects, metabolism)
• Heart Rate (drug effects)
• Hemoglobins (metabolism)
• Kidney Function Tests
• Male
• NADPH Oxidase 4
• NADPH Oxidases (biosynthesis)
• Nephrectomy
• Nitric Oxide Synthase Type III (metabolism)
• Nitroglycerin (pharmacology)
• Polyethylene Glycols (pharmacology)
• Proteinuria (urine)
• Rats
• Renal Insufficiency, Chronic (blood, metabolism, urine)
• Tyrosine (analogs & derivatives, metabolism)
• Ultrasonography
• Vasodilation (drug effects)