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Carbamylated erythropoietin-FC fusion protein and recombinant human erythropoietin during porcine kidney ischemia/reperfusion injury.

Abstract：

PURPOSE:To test the hypothesis that a carbamylated EPO-FC fusion protein (cEPO-FC) or recombinant human erythropoietin (rhEPO) would protect against kidney ischemia/reperfusion (I/R) injury in pigs with atherosclerosis. METHODS:Anesthetized and mechanically ventilated animals received cEPO-FC (50 μg kg(-1)), rhEPO (5,000 IU kg(-1)), or vehicle (n = 9 per group) prior to 120 min of aortic occlusion and over 4 h of reperfusion. During aortic occlusion, mean arterial pressure (MAP) was maintained at 80-120 % of baseline values by esmolol, nitroglycerin, and ATP. During reperfusion, noradrenaline was titrated to keep MAP at pre-ischemic levels. Blood creatinine and neutrophil gelatinase-associated lipocalin (NGAL) levels, creatinine clearance, fractional Na(+) excretion, and HE and PAS staining were used to assess kidney function and histological damage. Plasma interleukin-6, tumor necrosis factor-α, nitrate + nitrite and 8-isoprostane levels were measured to assess systemic inflammation, and nitrosative and oxidative stress. RESULTS:I/R caused acute kidney injury with reduced creatinine clearance, increased fractional Na(+) excretion and NGAL levels, moderate to severe glomerular and tubular damage and apoptosis, systemic inflammation and oxidative and nitrosative stress, but there were no differences between the treatment groups. Pre-ischemia nitrate + nitrite and 8-isoprostanes levels were lower and higher, respectively, than in healthy animals of a previous study, and immune histochemistry showed higher endothelial nitric oxide synthase and lower EPO receptor expression in pre-ischemia kidney biopsies than in biopsies from healthy animals. CONCLUSIONS:In swine with atherosclerosis, rhEPO and cEPO-FC failed to attenuate prolonged ischemia-induced kidney injury within an 8-h reperfusion period, possibly due to reduced EPO receptor expression resulting from pre-existing oxidative stress and/or reduced NO release.

journal_name

Intensive Care Med

journal_title

Intensive care medicine

authors

Matějková Š,Scheuerle A,Wagner F,McCook O,Matallo J,Gröger M,Seifritz A,Stahl B,Vcelar B,Calzia E,Georgieff M,Möller P,Schelzig H,Radermacher P,Simon F

doi

10.1007/s00134-012-2766-y

subject

Has Abstract

pub_date

2013-03-01 00:00:00

pages

497-510

issue

eissn

0342-4642

issn

1432-1238

journal_volume

pub_type

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Carbamylated erythropoietin-FC fusion protein and recombinant human erythropoietin during porcine kidney ischemia/reperfusion injury.