Kidney-intrinsic factors determine the severity of ischemia/reperfusion injury in a mouse model of delayed graft function.
Kidney-intrinsic factors determine the severity of ischemia/reperfusion injury in a mouse model of delayed graft function.
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DOI：
10.1016/j.kint.2020.07.033
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发表时间：
2020-12
影响因子：
19.6
通讯作者：
Zhang ZJ
中科院分区：
文献类型：
--
作者：
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
由于移植缺血/再灌注损伤导致的移植肾功能延迟对高达50%的已故供者肾移植受者造成不利影响。然而，影响缺血/再灌注损伤严重程度的关键因素仍不清楚。在这里，使用临床相关的移植物功能延迟的小鼠模型，我们证明供者的遗传背景和肾脏固有的MyD88/Trif依赖的先天免疫是移植物功能延迟的关键决定因素。移植肾功能恶化与冷缺血时间长短直接相关。冷缺血时间超过6h后，移植物功能障碍不可逆转。当冷缺血时间达到4小时时，移植肾表现出反映临床肾移植延迟移植功能的组织学特征。值得注意的是，无论受体品系或同种异体反应如何，B6小鼠的肾脏表现出明显比C3H或BALB/c小鼠肾脏更严重的组织学和功能损害。此外，B6小鼠的同种异体移植还显示出IL-6、中性粒细胞明胶酶相关的Lipocalin和内质网应激基因的上调，以及宿主中性粒细胞和记忆CD8 T细胞的增加。相反，供者MyD88/Trif缺陷抑制了中性粒细胞的流入，降低了IL-6和内质网应激基因的表达，改善了移植物的功能，延长了移植物的存活时间。因此，涉及遗传特征和先天免疫的肾脏内在因素是移植物功能延迟严重程度的关键决定因素。这种临床前的小鼠模型可以进一步研究移植物功能延迟的机制。
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.
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DOI：
10.1111/j.1600-6143.2012.04203.x
发表时间：
2012-11
期刊：
American journal of transplantation : official journal of the American Society of Transplantation and the American Society of Transplant Surgeons
影响因子：
--
作者：
Chen G;Kheradmand T;Bryant J;Wang S;Tasch J;Wang JJ;Zhang Z;Luo X
通讯作者：
Luo X
DOI：
10.3791/57718
发表时间：
2018-06-20
期刊：
Journal of visualized experiments : JoVE
影响因子：
--
作者：
Ding W;Yousefi K;Shehadeh LA
通讯作者：
Shehadeh LA
影响因子：
19.6
作者：
Inagi, R;Nangaku, M;Miyata, T
通讯作者：
Miyata, T
影响因子：
15.9
作者：
Aufhauser, David D., Jr.;Wang, Zhonglin;Levine, Matthew H.
通讯作者：
Levine, Matthew H.
影响因子：
19.6
作者：
Han, WK;Bailly, V;Bonventre, JV
通讯作者：
Bonventre, JV