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: Hiroe Toba, Masayuki Morishita, Chisato Tojo, Arisa Nakano, Yuko Oshima, Yushi Kojima, Mamiko Yoshida, Kohei Nakashima, Jiahong Wang, Miyuki Kobara, Tetsuo Nakata
• Journal: European journal of pharmacology (Eur J Pharmacol) Vol. 656 Issue 1-3 Pg. 81-7 (Apr 10 2011) ISSN: 1879-0712 [Electronic] Netherlands
• PMID: 21296066 (Publication Type: Journal Article)
• Copyright: Copyright © 2011 Elsevier B.V. All rights reserved.

Chemical References

• Nitrogen Oxides
• Phosphoproteins
• Recombinant Proteins
• Osteopontin
• Erythropoietin
• Nitroprusside
• nitrogen trioxide
• Nitric Oxide
• Nitric Oxide Synthase Type III
• Acetylcholine
• Nitrogen Dioxide

Topics

• Acetylcholine (pharmacology)
• Animals
• Aorta (drug effects, injuries, metabolism, physiopathology)
• Aorta, Thoracic (drug effects, pathology)
• Blood Pressure (drug effects)
• Body Weight (drug effects)
• Connective Tissue (drug effects, immunology)
• Dose-Response Relationship, Drug
• Endothelium, Vascular (drug effects, metabolism)
• Erythropoietin (pharmacology)
• Gene Expression Regulation, Enzymologic (drug effects)
• Hematocrit
• Hematopoiesis (drug effects)
• Humans
• Hypertension (blood, immunology, metabolism, physiopathology)
• Macrophages (drug effects, immunology)
• Male
• Nephrectomy
• Nitric Oxide (metabolism)
• Nitric Oxide Synthase Type III (metabolism)
• Nitrogen Dioxide (blood)
• Nitrogen Oxides (blood)
• Nitroprusside (pharmacology)
• Osteopontin (metabolism)
• Phosphoproteins (metabolism)
• Rats
• Rats, Wistar
• Recombinant Proteins (pharmacology)