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The mTORC2 Activation Is Critical for Hepato-Cytoprotection Against Ischemia and Reperfusion Injury.

H. Zhou,1,2 J. Zhu,1,3 S. Yue,1 R. Busuttil,1 J. Kupiec-Weglinski,1 X. Wang,2 Y. Zhai.1

1Surgery, David Geffen School of Medicine-University of California-Los Angeles, LA, CA
2Liver Surgery, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu Province, China
3Liver Surgery, Renji Hospital, Shanghai, China.

Meeting: 2016 American Transplant Congress

Abstract number: C115

Keywords: Hepatocytes, Ischemia, Liver, Rapamycin

Session Information

Date: Monday, June 13, 2016

Session Name: Poster Session C: Ischemia Reperfusion Injury and Organ Preservation

Session Time: 6:00pm-7:00pm

 Presentation Time: 6:00pm-7:00pm

Location: Halls C&D

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  • Distinctive Roles of mTORC1 Vs. mTORC2 in Liver Ischemia-Reperfusion Injury
  • Ischemia-Induced Endoplasmic Reticulum Stress Regulates Autophagy to Determine the Severity of Liver Ischemia Reperfusion Injury

Background & Aims

Rapamycin and Everolimus have been used in liver transplant patients, particularly those with calcineurin inhibitor-related nephrotoxicity and hepatocellular carcinoma. Although designed as mTORC1 inhibitors, they may interfere with mTORC2 functions when used chronically and at high doses. The biological consequences of mTORC2 inhibition in liver transplantation is not clear. We have shown in our previous study that inhibition of mTORC1, but not dual mTORC1/2, protected livers from ischemia and reperfusion injury by promoting hepatocyte survival against stress/inflammation. This study aims to determine roles of mTORC2 in liver IRI.

Methods

In a murine liver partial warm ischemia model (90m ischemia in cephalad lobes), mTORC1/2 activation by IR was determined by Western blot analysis of phosphorylations of their respective substrate S6K and Akt (S473). Gene knock-down of mTORC2-specific subunit Rictor was achieved in vivo by iv infection of host animals with adeno-associated viruses (AAV) carrying its shRNA expressing vectors; or in vitro by transfection of hepatocytes with its siRNA (conjugated with polymers).

Results

Liver ischemia transiently inactivated mTORC2, followed by its reactivation which was sustained throughout reperfusion. mTORC1 was only transiently activated during reperfusion. In mice infected with Rictor shRNA AAVs, liver Rictor expression was completely knock-down, as compared with those infected with control shRNA AAVs. Rictor knock-down resulted in exacerbation of liver IRI, measured at both 6h and 24h post reperfusion by sALT and histological analysis. In vitro, hepatocytes transfected with Raptor (mTORC1 specific subunit) or Rictor siRNA resulted in specific downregulation of Raptor or Rictor protein level, respectively. While Raptor knock-down protected hepatocytes from both stress (Thapsigargin-induced endoplasmic reticulum stress) and inflammation (TNF-a) -induced cell death, Rictor knock-down promoted both forms of cell death by enhancing caspase 3 activation.

Conclusions

Rictor/mTORC2 is a critical pro-survival signaling molecule in livers. mTORC2 inactivation by ischemia facilitates the development of liver IRI.

CITATION INFORMATION: Zhou H, Zhu J, Yue S, Busuttil R, Kupiec-Weglinski J, Wang X, Zhai Y. The mTORC2 Activation Is Critical for Hepato-Cytoprotection Against Ischemia and Reperfusion Injury. Am J Transplant. 2016;16 (suppl 3).

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To cite this abstract in AMA style:

Zhou H, Zhu J, Yue S, Busuttil R, Kupiec-Weglinski J, Wang X, Zhai Y. The mTORC2 Activation Is Critical for Hepato-Cytoprotection Against Ischemia and Reperfusion Injury. [abstract]. Am J Transplant. 2016; 16 (suppl 3). https://atcmeetingabstracts.com/abstract/the-mtorc2-activation-is-critical-for-hepato-cytoprotection-against-ischemia-and-reperfusion-injury/. Accessed February 28, 2021.

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