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

Rentsendorj, Otgonchimeg; Zhang, Xiaoyuan; Williams, Matthew; Buehler, Paul; D’Agnillo, Felice

doi:10.3390/toxics4010006

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

Journal Article · Fri Feb 19 00:00:00 EST 2016 · Toxics

DOI:https://doi.org/10.3390/toxics4010006· OSTI ID:1630032

Rentsendorj, Otgonchimeg ^[1]; Zhang, Xiaoyuan ^[1]; Williams, Matthew ^[1]; Buehler, Paul ^[1]; D’Agnillo, Felice ^[1]

U.S. Food and Drug Administration (FDA), Silver Spring, MD (United States). Center for Biologics Evaluation and Research. Division of Hematology Research and Review. Lab. of Biochemistry and Vascular Biology

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.

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Research Organization:: Oak Ridge Institute for Science and Education (ORISE), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER). Biological Systems Science Division

Grant/Contract Number:: SC0014664

OSTI ID:: 1630032

Journal Information:: Toxics, Vol. 4, Issue 1; ISSN 2305-6304

Publisher:: MDPICopyright Statement

Country of Publication:: United States

Language:: English

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

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