title: Epoetin beta pegol ameliorates flow-mediated dilation with improving endothelial nitric oxide synthase coupling state in nonobese diabetic rats.
abstract: OBJECTIVE
  Patients with diabetic nephropathy have a high cardiovascular mortality. Epoetin beta pegol (continuous erythropoietin receptor activator, C.E.R.A.) is a drug for the treatment of renal anemia. In this study, we investigated the effect of C.E.R.A. on vascular endothelial function as evaluated by flow-mediated dilation (FMD) and the relationship between hematopoiesis and FMD in diabetic nephropathy rats.
  
  
  METHODS
  Male Spontaneously Diabetic Torii rats (SDT, 22 weeks old) were used. C.E.R.A. (0.6, 1.2 μg/kg) was administered subcutaneously once every 2 weeks for 8 weeks. At 1 week after last administration (31 weeks old), we assessed FMD in the femoral arteries of anesthetized rats using a high-resolution ultrasound system. FMD was also measured 1 week after single C.E.R.A. treatment (5.0 μg/kg) to examine the influence of hematopoiesis.
  
  
  RESULTS
  Flow-mediated dilation was significantly decreased in SDT rats before the start of C.E.R.A. treatment (22 weeks old). Repeated administration of C.E.R.A. dose-dependently improved FMD in SDT rats (31 weeks old) without changing blood glucose, nitroglycerin-induced vasodilation, or kidney function. Long-term administration of C.E.R.A. improved the state of endothelial nitric oxide synthase uncoupling in the femoral arteries of SDT rats, which showed a positive correlation with FMD. On the other hand, there was no correlation between FMD and Hb or Hct in SDT rats. Furthermore, at 1 week after single administration of C.E.R.A., FMD was not significantly improved although hemoglobin levels were comparable with levels following long-term C.E.R.A.
  
  
  METHODS
  
  
  
  CONCLUSIONS
  Long-term treatment with C.E.R.A. improved FMD in SDT rats even after onset of endothelial dysfunction.
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd, Shizuoka, Japan.
authors.forename: Kenichi
authors.identifier: http://orcid.org/0000-0001-5330-441X
authors.initials: K
authors.lastname: Serizawa
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd, Shizuoka, Japan.
authors.forename: Kenji
authors.initials: K
authors.lastname: Yogo
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd, Kanagawa, Japan.
authors.forename: Yoshihito
authors.initials: Y
authors.lastname: Tashiro
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd, Kanagawa, Japan.
authors.forename: Ryohei
authors.initials: R
authors.lastname: Kawasaki
authors.affiliation: Medical Science Department, Chugai Pharmaceutical Co., Ltd, Tokyo, Japan.
authors.forename: Koichi
authors.initials: K
authors.lastname: Endo
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd, Kanagawa, Japan.
authors.forename: Yasushi
authors.initials: Y
authors.lastname: Shimonaka
authors.affiliation: Product Research Department, Chugai Pharmaceutical Co., Ltd, Kanagawa, Japan.
authors.forename: Michinori
authors.initials: M
authors.lastname: Hirata
mesh_terms: D000818:Animals; D015415:Biomarkers / Q000097:blood; D003920:Diabetes Mellitus / Q000097:blood / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004730:Endothelium, Vascular / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D004921:Erythropoietin / Q000494:pharmacology*; D005263:Femoral Artery / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D006410:Hematopoiesis / Q000187:drug effects; D006454:Hemoglobins / Q000378:metabolism; D008297:Male; D052250:Nitric Oxide Synthase Type III / Q000378:metabolism*; D011092:Polyethylene Glycols / Q000494:pharmacology*; D011919:Rats, Inbred Strains; D020127:Recovery of Function; D015398:Signal Transduction / Q000187:drug effects; D013997:Time Factors; D014664:Vasodilation / Q000187:drug effects*
chemical_list: D015415:Biomarkers; D006454:Hemoglobins; C508420:continuous erythropoietin receptor activator; D004921:Erythropoietin; D011092:Polyethylene Glycols; D052250:Nitric Oxide Synthase Type III; C496316:Nos3 protein, rat
keywords: Chronic kidney disease; Diabetic nephropathy; Endothelial dysfunction; Epoetin beta pegol; Erythropoietin-stimulating agents; Flow-mediated dilation