Darbepoetin Alpha Reduces Oxidative Stress and Chronic Inflammation in Atherosclerotic Lesions of Apo E Deficient Mice in Experimental Renal Failure

Abstract

BackgroundCardiovascular 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.MethodsApo 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.ResultsBoth 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.ConclusionDarbepoetin 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.

Possible Inhibitory Effect of Erythropoiesis-Stimulating Agents at the Predialysis Stage on Early-Phase Coronary Events after Hemodialysis Initiation

“…Epo diminished the production of inflammatory cytokines [18] and oxidative stress [19] and had beneficial effects on the morphology of atherosclerotic lesions of apo E knockout mice via reduction of the lipid content of macrophages and the subsequent formation of foam cells [20]. Darbepoetin alpha, a long-acting ESA, suppressed oxidative stress, inflammation in the heart and aorta, plaque stage, and plaque cholesterol content in subtotally nephrectomized rats [21]. The positive association of nonuse of ESA from the predialysis stage with obstructive CAD needing coronary revascularization found in this study would indicate the inhibitory effect of ESA on the progression of coronary plaque.…”

Effects of Long- and Short-term Darbepoetin-α Treatment on Oxidative Stress, Inflammation and Endothelial Injury in Apo E Knockout Mice

“…23 In accordance with our findings, Arend et al reported a significant decrease in CRP expression in darbepoetin-α-treated ApoE -/mice. 24 In a study performed by Huang et al it was reported that basal serum IL-6 levels of ApoE knockout mice were akin to those in C57BL mice. 25 Histamine and its receptors are formed in atherosclerotic lesions, and their signaling and following proinflammatory and proatherogenic gene expression are involved in the progress of atherogenesis.…”

“…Arend et al reported that ICAM protein expression in the aorta did not differ markedly between the nephrectomized or darbepoetin-α-treated groups, neither in the intramyocardial arteries and aortic plaque nor in the aortic endothelium of ApoE -/mice. 24 Endothelial function is impaired in the earlier stages of atherogenesis and is strongly correlated with several risk factors. Endothelial dysfunction predisposes to longterm atherosclerotic lesions and has been proposed as an important diagnostic and prognostic factor.…”

Comparison of the Hypazotemic Effects of Erythropoietin and U-74389G on Urea Levels

“…Aizawa et al suppressed [33] increased urea nitrogen after epoetin beta pegol (CERA) in Thy-1-GN rats. Arend et al [34] considered the dose-dependent adverse effects of high darbepoetin treatment as elevated serum urea in nephrectomized apo E knockout mice. Ahmadiasl et al significantly decreased [35] blood SOD, GPx, and urea levels and increased TAC level after treatment with Epo and MEL in renal IR injury of male rats.…”