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.
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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U2 - 10.1016/j.kint.2020.07.033
DO - 10.1016/j.kint.2020.07.033
M3 - Article
C2 - 32822703
AN - SCOPUS:85095834552
VL - 98
SP - 1489
EP - 1501
JO - Kidney International
JF - Kidney International
SN - 0085-2538
IS - 6
ER -