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Toxics 2016, 4(1), 6; doi:10.3390/toxics4010006

Transcriptional Suppression of Renal Antioxidant Enzyme Systems in Guinea Pigs Exposed to Polymerized Cell-Free Hemoglobin

Laboratory of Biochemistry and Vascular Biology, Division of Hematology Research and Review, Center for Biologics Evaluation and Research, Food and Drug Administration, Silver Spring, MD 20993, USA
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Academic Editors: Guido Cavaletti and Valentina Carozzi
Received: 14 January 2016 / Revised: 3 February 2016 / Accepted: 4 February 2016 / Published: 19 February 2016
(This article belongs to the Special Issue Toxicities of Therapeutic Agents Used in Medicine)
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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. View Full-Text
Keywords: hemoglobin-based oxygen carrier (HBOC); kidney; oxidative stress; antioxidants; DNA methylation hemoglobin-based oxygen carrier (HBOC); kidney; oxidative stress; antioxidants; DNA methylation
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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. (CC BY 4.0).

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MDPI and ACS Style

Rentsendorj, O.; Zhang, X.; Williams, M.C.; Buehler, P.W.; D’Agnillo, F. Transcriptional Suppression of Renal Antioxidant Enzyme Systems in Guinea Pigs Exposed to Polymerized Cell-Free Hemoglobin. Toxics 2016, 4, 6.

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