Abstract
Hemoglobin-based oxygen carriers (HBOCs) are being developed as oxygen and plasma volume-expanding therapeutics though their potential to promote oxidative tissue injury has raised safety concerns. Using a guinea pig exchange transfusion model, we examined the effects of polymerized bovine hemoglobin (HbG) on the transcriptional regulation, activity, and expression of the renal antioxidant enzymes; superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx). HbG infusion downregulated the mRNA levels for genes encoding SOD isoforms 1-3, GPx1, GPx3, GPx4, and CAT. This transcriptional suppression correlated with decreased enzymatic activities for SOD, CAT, and GPx. Immunostaining revealed decreased protein expression of SOD1, CAT, and GPx1 primarily in renal cortical tubules. DNA methylation analyses identified CpG hypermethylation in the gene promoters for SOD1-3, GPx1, GPx3, and GPx4, suggesting an epigenetic-based mechanism underlying the observed gene repression. HbG also induced oxidative stress as evidenced by increased renal lipid peroxidation end-products and 4-HNE immunostaining, which could be the result of the depleted antioxidant defenses and/or serve as a trigger for increased DNA methylation. Together, these findings provide evidence that the renal exposure to HbG suppresses the function of major antioxidant defense systems which may have relevant implications for understanding the safety of hemoglobin-based products.
Highlights
Modified or recombinant hemoglobin (Hb)-based oxygen carriers (HBOCs) are being developed as oxygen and volume replacement therapy for clinical indications such as emergency resuscitation, elective surgery, organ perfusion, and others [1,2]
We reported that polymerized Hb transfusion in guinea pigs triggers blood brain barrier (BBB) disruption characterized by alterations in cerebral endothelial tight junctions, increased BBB permeability, astrocyte and perivascular cell activation, and increased oxidative markers including heme oxygenase-1 (HO-1) and lipid peroxidation end products [4]
Using a guinea pig exchange transfusion (ET) model, we examined the effects of polymerized bovine hemoglobin (HbG) on the transcriptional regulation, activity, and expression of the renal antioxidant enzymes; superoxide dismutase (SOD), catalase (CAT), and glutathione peroxidase (GPx)
Summary
Modified or recombinant hemoglobin (Hb)-based oxygen carriers (HBOCs) are being developed as oxygen and volume replacement therapy for clinical indications such as emergency resuscitation, elective surgery, organ perfusion, and others [1,2]. HBOCs have several potential benefits over red blood cells (RBCs) including universal compatibility, immediate availability, and long-term storage. Despite these important advantages, HBOC development in the United States has been slowed by safety concerns prompted by reports of serious adverse events, including death, in late phase clinical trials [2,3]. We reported that polymerized Hb transfusion in guinea pigs triggers blood brain barrier (BBB) disruption characterized by alterations in cerebral endothelial tight junctions, increased BBB permeability, astrocyte and perivascular cell activation, and increased oxidative markers including heme oxygenase-1 (HO-1) and lipid peroxidation end products [4]. Renal exposure to oxidized human Hb increased nuclear factor erythroid 2-derived-factor 2 (Nrf-2) and HO-1 expression, non-heme iron deposition, lipid peroxidation, interstitial inflammatory cell activation, and tubular and glomerular injury markers [5]
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