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

نویسندگان

  • Otgonchimeg Rentsendorj
  • Xiaoyuan Zhang
  • Matthew C. Williams
  • Paul W. Buehler
  • Felice D'Agnillo
چکیده

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.

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

منابع مشابه

Suppression of severe airway inflammation with non-toxic dietary nutrients in histamine-challenged guinea pigs: A comparison with Ibuprofen

We hypothesize that selected combinations of nutrients commonly encountered in the human diet, suppress asthma-associated airway inflammation more effectively than currently available anti-inflammatory medications. Here we demonstrate that biflavones and terpenes, distributed widely in human diet (in this case derived from Ginkgo biloba) synergize with the carotenoid antioxidant astaxanthin and...

متن کامل

Suppression of severe airway inflammation with non-toxic dietary nutrients in histamine-challenged guinea pigs: A comparison with Ibuprofen

We hypothesize that selected combinations of nutrients commonly encountered in the human diet, suppress asthma-associated airway inflammation more effectively than currently available anti-inflammatory medications. Here we demonstrate that biflavones and terpenes, distributed widely in human diet (in this case derived from Ginkgo biloba) synergize with the carotenoid antioxidant astaxanthin and...

متن کامل

Effects of endogenous ascorbate on oxidation, oxygenation, and toxicokinetics of cell-free modified hemoglobin after exchange transfusion in rat and guinea pig.

Chemically modified hemoglobin (Hb) solutions are promising oxygen therapeutics; however, these agents are prone to intravascular oxidation. Using a 50% exchange transfusion (ET) model with bovine polymerized hemoglobin (PolyHbBv), we examined heme oxidation, oxygenation markers, and toxicokinetics in rats, an ascorbic acid (AA)-producing species, and in guinea pigs, a non-AA-producing species....

متن کامل

Effect of vitamin C on tracheal responsiveness and pulmonary inflammation in chronic obstructive pulmonary disease model of guinea pig

Introduction: In the present study, the prophylactic effect of vitamin C, as a potent anti-oxidant, on tracheal responsiveness to methacholine and ovalbumin, bronchoalveolar lavage fluid white blood cell (WBC) count and differential count, and also lung pathology in chronic obstructive pulmonary disease (COPD) -guinea pigs (cigarette exposed guinea pigs) were examined. In addition, the relax...

متن کامل

The Effect of Celecoxib, a Cyclooxygenase-2 Inhibitor on Noise- Induced Hearing Loss

Objective(s): Noise-induced hearing loss (NIHL) is the major cause of acquired hearing loss.  Celecoxib, a cyclooxygenase-2 (COX-2) inhibitor, is a non- steroidal anti- inflammatory drug (NSAID) with known antioxidant and antineoplastic activity. Therefore, we monitored the extent of temporary noise- induced threshold shifts (TTS) and cochlear damage caused by high level 4- kHz noise exposure t...

متن کامل

ذخیره در منابع من


  با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید

برای دانلود متن کامل این مقاله و بیش از 32 میلیون مقاله دیگر ابتدا ثبت نام کنید

ثبت نام

اگر عضو سایت هستید لطفا وارد حساب کاربری خود شوید

عنوان ژورنال:

دوره 4  شماره 

صفحات  -

تاریخ انتشار 2016