Assessment of Hepatic Ischemia-Reperfusion Injuries by NRF2-Dependent Transcriptional Activities of Bile Transporters in Rats
1Surgery, Medical College of Wisconsin, Milwaukee, WI
2Physiology, Medical College of Wisconsin, Milwaukee, WI
3Pathology, Johns Hopkins University School of Medicine, Baltimore, MD.
Meeting: 2018 American Transplant Congress
Abstract number: A31
Keywords: Ischemia, Liver grafts, Oxidant stress, Preservation
Session Information
Session Name: Poster Session A: Biomarkers, Immune Monitoring and Outcomes
Session Type: Poster Session
Date: Saturday, June 2, 2018
Session Time: 5:30pm-7:30pm
Presentation Time: 5:30pm-7:30pm
Location: Hall 4EF
Background: The effect of hepatic ischemia and reperfusion injury (IRI) on bile transporter (BT) gene expression and the role of Nrf2 in BT regulation during the process of IRI are unknown. We hypothesized that the abnormal expression of Nrf2 and BTs during the ischemic stage of hepatic IRI contributes to the pathophysiology of cholestasis after reperfusion.
Methods: Sham surgery and short (60 min) or long (90min) periods of warm ischemia time (WIT) with or without reperfusion for 24 h were applied to wild-type Sprague-Dawley rats and Nrf2 knockout rats (n=40, 5 per group). At each stage of IRI, the serum levels of aminotransferase, total bilirubin, and bile acids were measured. Hepatic tissue was also sampled for adenosine triphosphate (ATP) measurements and the quantitative real-time polymerase chain reactions of BTs (Oatp1, Ntcp, Mrp2, Bsep, and Mrp3).
Results: The BT expressions demonstrated a significant correlation with Nrf2 expressions. When WIT was short, the BT expressions increased during the ischemia stage and returned to the baseline after reperfusion. However, when WIT was long, the BT expressions decreased further after reperfusion. The effect of short WIT did not occur in Nrf2 knockout animals. The levels of BT expressions were correlated with the histologic score of IRI (Suzuki score), the serum levels of aminotransferases, bilirubin and bile acids, and the tissue ATP level. Stepwise multiple regression analyses derived equations to predict the Suzuki score (R2 = 76.8, P < 0.001), serum total bilirubin (R2 = 61.2, P < 0.001), and tissue ATP (R2 = 61.1, P < 0.001).
Conclusion: While long WIT decreases transcriptional activities of BTs, short WIT increases the transcriptional activity of BTs in a NRF2-dependent manner, and thus prevents cholestasis after reperfusion. BT expressions can be surrogate markers and therapeutic indicators of hepatic IRI.
CITATION INFORMATION: Kim J., Martin A., Yee J., Fojut L., Geurts A., Oshima K., Zimmerman M., Hong J. Assessment of Hepatic Ischemia-Reperfusion Injuries by NRF2-Dependent Transcriptional Activities of Bile Transporters in Rats Am J Transplant. 2017;17 (suppl 3).
To cite this abstract in AMA style:
Kim J, Martin A, Yee J, Fojut L, Geurts A, Oshima K, Zimmerman M, Hong J. Assessment of Hepatic Ischemia-Reperfusion Injuries by NRF2-Dependent Transcriptional Activities of Bile Transporters in Rats [abstract]. https://atcmeetingabstracts.com/abstract/assessment-of-hepatic-ischemia-reperfusion-injuries-by-nrf2-dependent-transcriptional-activities-of-bile-transporters-in-rats/. Accessed May 8, 2025.« Back to 2018 American Transplant Congress