Kidney-intrinsic factors determine the severity of ischemia/reperfusion injury in a mouse model of delayed graft function

Longhui Qiu; Xingqiang Lai; Jiao jing Wang; Xin Yi Yeap; Shulin Han; Feibo Zheng; Charlie Lin; Zhuoli Zhang; Daniele Procissi; Deyu Fang; Lin Li; Edward B. Thorp; Michael M. Abecassis; Yashpal S. Kanwar; Zheng J. Zhang

doi:10.1016/j.kint.2020.07.033

Kidney-intrinsic factors determine the severity of ischemia/reperfusion injury in a mouse model of delayed graft function

Longhui Qiu, Xingqiang Lai, Jiao jing Wang, Xin Yi Yeap, Shulin Han, Feibo Zheng, Charlie Lin, Zhuoli Zhang, Daniele Procissi, Deyu Fang, Lin Li, Edward B. Thorp, Michael M. Abecassis, Yashpal S. Kanwar, Zheng J. Zhang^*

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

16 Scopus citations

Abstract

Delayed graft function due to transplant ischemia/reperfusion injury adversely affects up to 50% of deceased-donor kidney transplant recipients. However, key factors contributing to the severity of ischemia/reperfusion injury remain unclear. Here, using a clinically relevant mouse model of delayed graft function, we demonstrated that donor genetic background and kidney-intrinsic MyD88/Trif-dependent innate immunity were key determinants of delayed graft function. Functional deterioration of kidney grafts directly corresponded with the duration of cold ischemia time. The graft dysfunction became irreversible after cold ischemia time exceeded six hours. When cold ischemia time reached four hours, kidney grafts displayed histological features reflective of delayed graft function seen in clinical kidney transplantation. Notably, kidneys of B6 mice exhibited significantly more severe histological and functional impairment than kidneys of C3H or BALB/c mice, regardless of recipient strains or alloreactivities. Furthermore, allografts of B6 mice also showed an upregulation of IL-6, neutrophil gelatinase-associated lipocalin, and endoplasmic reticulum stress genes, as well as an increased influx of host neutrophils and memory CD8 T-cells. In contrast, donor MyD88/Trif deficiency inhibited neutrophil influx and decreased the expression of IL-6 and endoplasmic reticulum stress genes, along with improved graft function and prolonged allograft survival. Thus, kidney-intrinsic factors involving genetic characteristics and innate immunity serve as critical determinants of the severity of delayed graft function. This preclinical murine model allows for further investigations of the mechanisms underlying delayed graft function.

Original language	English (US)
Pages (from-to)	1489-1501
Number of pages	13
Journal	Kidney international
Volume	98
Issue number	6
DOIs	https://doi.org/10.1016/j.kint.2020.07.033
State	Published - Dec 2020

Funding

The authors thank William A. Muller, MD, PhD, Professor of Pathology at Northwestern University, and Mary Hummel, PhD, for reviewing the manuscript and constructive suggestions. This study is supported by National Institutes of Health grants P01 P01AI112522 (EBT, MMA, ZJZ) and DK60635 (YSK). Histology services were provided by the Northwestern University Research Histology and Phenotyping Laboratory, which is supported by National Cancer Institute grant P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. We thank the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, IL, for the use of the Flow Cytometry Core Facility. Surgical services were provided by the Northwestern University Comprehensive Transplant Center Microsurgery Core. Functional MRI was performed at the small Animal Imaging Core in the Center for Translational Imaging Northwestern University.

Keywords

delayed graft function
donor factors
innate immunity
ischemia/reperfusion injury
kidney transplantation
mouse model

ASJC Scopus subject areas

Nephrology

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Qiu, L., Lai, X., Wang, J. J., Yeap, X. Y., Han, S., Zheng, F., Lin, C., Zhang, Z., Procissi, D., Fang, D., Li, L., Thorp, E. B., Abecassis, M. M., Kanwar, Y. S., & Zhang, Z. J. (2020). Kidney-intrinsic factors determine the severity of ischemia/reperfusion injury in a mouse model of delayed graft function. Kidney international, 98(6), 1489-1501. https://doi.org/10.1016/j.kint.2020.07.033

@article{6ef4dbef5a2445208bb1ae35dfafdf90,

title = "Kidney-intrinsic factors determine the severity of ischemia/reperfusion injury in a mouse model of delayed graft function",

abstract = "Delayed graft function due to transplant ischemia/reperfusion injury adversely affects up to 50% of deceased-donor kidney transplant recipients. However, key factors contributing to the severity of ischemia/reperfusion injury remain unclear. Here, using a clinically relevant mouse model of delayed graft function, we demonstrated that donor genetic background and kidney-intrinsic MyD88/Trif-dependent innate immunity were key determinants of delayed graft function. Functional deterioration of kidney grafts directly corresponded with the duration of cold ischemia time. The graft dysfunction became irreversible after cold ischemia time exceeded six hours. When cold ischemia time reached four hours, kidney grafts displayed histological features reflective of delayed graft function seen in clinical kidney transplantation. Notably, kidneys of B6 mice exhibited significantly more severe histological and functional impairment than kidneys of C3H or BALB/c mice, regardless of recipient strains or alloreactivities. Furthermore, allografts of B6 mice also showed an upregulation of IL-6, neutrophil gelatinase-associated lipocalin, and endoplasmic reticulum stress genes, as well as an increased influx of host neutrophils and memory CD8 T-cells. In contrast, donor MyD88/Trif deficiency inhibited neutrophil influx and decreased the expression of IL-6 and endoplasmic reticulum stress genes, along with improved graft function and prolonged allograft survival. Thus, kidney-intrinsic factors involving genetic characteristics and innate immunity serve as critical determinants of the severity of delayed graft function. This preclinical murine model allows for further investigations of the mechanisms underlying delayed graft function.",

keywords = "delayed graft function, donor factors, innate immunity, ischemia/reperfusion injury, kidney transplantation, mouse model",

author = "Longhui Qiu and Xingqiang Lai and Wang, {Jiao jing} and Yeap, {Xin Yi} and Shulin Han and Feibo Zheng and Charlie Lin and Zhuoli Zhang and Daniele Procissi and Deyu Fang and Lin Li and Thorp, {Edward B.} and Abecassis, {Michael M.} and Kanwar, {Yashpal S.} and Zhang, {Zheng J.}",

note = "Funding Information: The authors thank William A. Muller, MD, PhD, Professor of Pathology at Northwestern University, and Mary Hummel, PhD, for reviewing the manuscript and constructive suggestions. This study is supported by National Institutes of Health grants P01 P01AI112522 (EBT, MMA, ZJZ) and DK60635 (YSK). Histology services were provided by the Northwestern University Research Histology and Phenotyping Laboratory, which is supported by National Cancer Institute grant P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. We thank the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, IL, for the use of the Flow Cytometry Core Facility. Surgical services were provided by the Northwestern University Comprehensive Transplant Center Microsurgery Core. Functional MRI was performed at the small Animal Imaging Core in the Center for Translational Imaging Northwestern University. Publisher Copyright: {\textcopyright} 2020 International Society of Nephrology",

year = "2020",

month = dec,

doi = "10.1016/j.kint.2020.07.033",

language = "English (US)",

volume = "98",

pages = "1489--1501",

journal = "Kidney international",

issn = "0085-2538",

publisher = "Elsevier B.V.",

number = "6",

}

Qiu, L, Lai, X, Wang, JJ, Yeap, XY, Han, S, Zheng, F, Lin, C, Zhang, Z, Procissi, D , Fang, D, Li, L, Thorp, EB, Abecassis, MM, Kanwar, YS & Zhang, ZJ 2020, 'Kidney-intrinsic factors determine the severity of ischemia/reperfusion injury in a mouse model of delayed graft function', Kidney international, vol. 98, no. 6, pp. 1489-1501. https://doi.org/10.1016/j.kint.2020.07.033

TY - JOUR

T1 - Kidney-intrinsic factors determine the severity of ischemia/reperfusion injury in a mouse model of delayed graft function

AU - Qiu, Longhui

AU - Lai, Xingqiang

AU - Wang, Jiao jing

AU - Yeap, Xin Yi

AU - Han, Shulin

AU - Zheng, Feibo

AU - Lin, Charlie

AU - Zhang, Zhuoli

AU - Procissi, Daniele

AU - Fang, Deyu

AU - Li, Lin

AU - Thorp, Edward B.

AU - Abecassis, Michael M.

AU - Kanwar, Yashpal S.

AU - Zhang, Zheng J.

N1 - Funding Information: The authors thank William A. Muller, MD, PhD, Professor of Pathology at Northwestern University, and Mary Hummel, PhD, for reviewing the manuscript and constructive suggestions. This study is supported by National Institutes of Health grants P01 P01AI112522 (EBT, MMA, ZJZ) and DK60635 (YSK). Histology services were provided by the Northwestern University Research Histology and Phenotyping Laboratory, which is supported by National Cancer Institute grant P30-CA060553 awarded to the Robert H. Lurie Comprehensive Cancer Center. We thank the Robert H. Lurie Comprehensive Cancer Center of Northwestern University in Chicago, IL, for the use of the Flow Cytometry Core Facility. Surgical services were provided by the Northwestern University Comprehensive Transplant Center Microsurgery Core. Functional MRI was performed at the small Animal Imaging Core in the Center for Translational Imaging Northwestern University. Publisher Copyright: © 2020 International Society of Nephrology

PY - 2020/12

Y1 - 2020/12

N2 - Delayed graft function due to transplant ischemia/reperfusion injury adversely affects up to 50% of deceased-donor kidney transplant recipients. However, key factors contributing to the severity of ischemia/reperfusion injury remain unclear. Here, using a clinically relevant mouse model of delayed graft function, we demonstrated that donor genetic background and kidney-intrinsic MyD88/Trif-dependent innate immunity were key determinants of delayed graft function. Functional deterioration of kidney grafts directly corresponded with the duration of cold ischemia time. The graft dysfunction became irreversible after cold ischemia time exceeded six hours. When cold ischemia time reached four hours, kidney grafts displayed histological features reflective of delayed graft function seen in clinical kidney transplantation. Notably, kidneys of B6 mice exhibited significantly more severe histological and functional impairment than kidneys of C3H or BALB/c mice, regardless of recipient strains or alloreactivities. Furthermore, allografts of B6 mice also showed an upregulation of IL-6, neutrophil gelatinase-associated lipocalin, and endoplasmic reticulum stress genes, as well as an increased influx of host neutrophils and memory CD8 T-cells. In contrast, donor MyD88/Trif deficiency inhibited neutrophil influx and decreased the expression of IL-6 and endoplasmic reticulum stress genes, along with improved graft function and prolonged allograft survival. Thus, kidney-intrinsic factors involving genetic characteristics and innate immunity serve as critical determinants of the severity of delayed graft function. This preclinical murine model allows for further investigations of the mechanisms underlying delayed graft function.

AB - Delayed graft function due to transplant ischemia/reperfusion injury adversely affects up to 50% of deceased-donor kidney transplant recipients. However, key factors contributing to the severity of ischemia/reperfusion injury remain unclear. Here, using a clinically relevant mouse model of delayed graft function, we demonstrated that donor genetic background and kidney-intrinsic MyD88/Trif-dependent innate immunity were key determinants of delayed graft function. Functional deterioration of kidney grafts directly corresponded with the duration of cold ischemia time. The graft dysfunction became irreversible after cold ischemia time exceeded six hours. When cold ischemia time reached four hours, kidney grafts displayed histological features reflective of delayed graft function seen in clinical kidney transplantation. Notably, kidneys of B6 mice exhibited significantly more severe histological and functional impairment than kidneys of C3H or BALB/c mice, regardless of recipient strains or alloreactivities. Furthermore, allografts of B6 mice also showed an upregulation of IL-6, neutrophil gelatinase-associated lipocalin, and endoplasmic reticulum stress genes, as well as an increased influx of host neutrophils and memory CD8 T-cells. In contrast, donor MyD88/Trif deficiency inhibited neutrophil influx and decreased the expression of IL-6 and endoplasmic reticulum stress genes, along with improved graft function and prolonged allograft survival. Thus, kidney-intrinsic factors involving genetic characteristics and innate immunity serve as critical determinants of the severity of delayed graft function. This preclinical murine model allows for further investigations of the mechanisms underlying delayed graft function.

KW - delayed graft function

KW - donor factors

KW - innate immunity

KW - ischemia/reperfusion injury

KW - kidney transplantation

KW - mouse model

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VL - 98

SP - 1489

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ER -

Kidney-intrinsic factors determine the severity of ischemia/reperfusion injury in a mouse model of delayed graft function

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