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.

• Authors: Šárka Matějková, Angelika Scheuerle, Florian Wagner, Oscar McCook, José Matallo, Michael Gröger, Andrea Seifritz, Bettina Stahl, Brigitta Vcelar, Enrico Calzia, Michael Georgieff, Peter Möller, Hubert Schelzig, Peter Radermacher, Florian Simon
• Journal: Intensive care medicine (Intensive Care Med) Vol. 39 Issue 3 Pg. 497-510 (Mar 2013) ISSN: 1432-1238 [Electronic] United States
• PMID: 23291730 (Publication Type: Journal Article)

Chemical References

• Immunoglobulin G
• Recombinant Proteins
• carbamylated erythropoietin
• Erythropoietin

Topics

• Animals
• Erythropoietin (analogs & derivatives, therapeutic use)
• Immunoglobulin G (therapeutic use)
• Kidney (blood supply)
• Male
• Recombinant Proteins (therapeutic use)
• Reperfusion Injury (prevention & control)
• Swine