title: Darbepoetin alpha reduces oxidative stress and chronic inflammation in atherosclerotic lesions of apo E deficient mice in experimental renal failure.
abstract: BACKGROUND
  Cardiovascular morbidity and mortality is very important in patients with chronic renal failure. This occurs even in mild impairment of renal function and may be related to oxidative stress and chronic inflammation. The nephrectomized apo E knockout mouse is an accepted model for evaluating atherosclerosis in renal dysfunction. Erythropoietin derivates showed anti-oxidative and anti-inflammatory effects. Therefore, this study evaluates the effects of Darbepoetin on markers of oxidative stress and chronic inflammation in atherosclerotic lesions in apo E knockout mice with renal dysfunction.
  
  
  METHODS
  Apo E knockout mice underwent unilateral (Unx, n = 20) or subtotal (Snx, n = 26) nephrectomy or sham operation (Sham, n = 16). Mice of each group were either treated with Darbepoetin or saline solution, a part of Snx mice received a tenfold higher dose of Darbepoetin. The aortic plaques were measured and morphologically characterized. Additional immunhistochemical analyses were performed on tissue samples taken from the heart and the aorta.
  
  
  RESULTS
  Both Unx and Snx mice showed increased expression of markers of oxidative stress and chronic inflammation. While aortic plaque size was not different, Snx mice showed advanced plaque stages when compared to Unx mice. Darbepoetin treatment elevated hematocrit and lowered Nitrotyrosin as one marker of oxidative stress, inflammation in heart and aorta, plaque stage and in the high dose even plaque cholesterol content. In contrast, there was no influence of Darbepoetin on aortic plaque size; high dose Darbepoetin treatment resulted in elevated renal serum parameters.
  
  
  CONCLUSIONS
  Darbepoetin showed some protective cardiovascular effects irrespective of renal function, i.e. it improved plaque structure and reduced some signs of oxidative stress and chronic inflammation without affecting plaque size. Nevertheless, the dose dependent adverse effects must be considered as high Darbepoetin treatment elevated serum urea. Elevation of hematocrit might be a favorable effect in anemic Snx animals but a thrombogenic risk in Sham animals.
authors.affiliation: Department of Internal Medicine- Nephrology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Nicole
authors.initials: N
authors.lastname: Arend
authors.affiliation: Department of Internal Medicine- Nephrology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Karl F
authors.initials: KF
authors.lastname: Hilgers
authors.affiliation: Department of Nephropathology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Valentina
authors.initials: V
authors.lastname: Campean
authors.affiliation: Department of Nephropathology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Britta
authors.initials: B
authors.lastname: Karpe
authors.affiliation: Department of Internal Medicine- Nephrology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Nada
authors.initials: N
authors.lastname: Cordasic
authors.affiliation: Department of Internal Medicine- Nephrology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Bernd
authors.initials: B
authors.lastname: Klanke
authors.affiliation: Department of Nephropathology, University of Erlangen-Nürnberg, Erlangen, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Amann
mesh_terms: D000818:Animals; D001057:Apolipoproteins E / Q000172:deficiency* / Q000235:genetics; D050197:Atherosclerosis / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D000068256:Darbepoetin alfa; D004921:Erythropoietin / Q000031:analogs & derivatives* / Q000627:therapeutic use; D007249:Inflammation / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D018384:Oxidative Stress / Q000187:drug effects / Q000235:genetics; D051437:Renal Insufficiency / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism*
chemical_list: D001057:Apolipoproteins E; D004921:Erythropoietin; D000068256:Darbepoetin alfa