NLRP3 inflammasome of renal tubular epithelial cells induces kidney injury in acute hemolytic transfusion reactions
Abstract Background Blood transfusion, a common basic supporting therapy, can lead to acute hemolytic transfusion reaction (AHTR). AHTR poses a great risk to patients through kidney function damage in a short time. Previous reports found that heme from destroyed red blood cells impaired kidney funct...
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doaj-fba334084bee421db0a6ebf7330e78a72021-03-30T14:25:36ZengWileyClinical and Translational Medicine2001-13262021-03-01113n/an/a10.1002/ctm2.373NLRP3 inflammasome of renal tubular epithelial cells induces kidney injury in acute hemolytic transfusion reactionsZhixin Liu0Yaozhen Chen1Bing Niu2Dandan Yin3Fan Feng4Shunli Gu5Qunxing An6Jinmei Xu7Ning An8Jing Zhang9Jing Yi10Wen Yin11Xiangyang Qin12Xingbin Hu13Department of Transfusion Medicine, Xijing Hospital Fourth Military Medical University Xi'an Shaanxi ChinaDepartment of Transfusion Medicine, Xijing Hospital Fourth Military Medical University Xi'an Shaanxi ChinaSchool of Life Sciences Shanghai University Shanghai ChinaDepartment of Hematology, Tangdu Hospital Fourth Military Medical University Xi'an Shaanxi ChinaDivision of Digestive Surgery, Xijing Hospital of Digestive Diseases Fourth Military Medical University Xian Shaanxi ChinaDepartment of Transfusion Medicine, Xijing Hospital Fourth Military Medical University Xi'an Shaanxi ChinaDepartment of Transfusion Medicine, Xijing Hospital Fourth Military Medical University Xi'an Shaanxi ChinaDepartment of Transfusion Medicine, Xijing Hospital Fourth Military Medical University Xi'an Shaanxi ChinaDepartment of Transfusion Medicine, Xijing Hospital Fourth Military Medical University Xi'an Shaanxi ChinaDepartment of Transfusion Medicine, Xijing Hospital Fourth Military Medical University Xi'an Shaanxi ChinaDepartment of Transfusion Medicine, Xijing Hospital Fourth Military Medical University Xi'an Shaanxi ChinaDepartment of Transfusion Medicine, Xijing Hospital Fourth Military Medical University Xi'an Shaanxi ChinaDepartment of Chemistry, School of Pharmacy Fourth Military Medical University Xi'an Shaanxi ChinaDepartment of Transfusion Medicine, Xijing Hospital Fourth Military Medical University Xi'an Shaanxi ChinaAbstract Background Blood transfusion, a common basic supporting therapy, can lead to acute hemolytic transfusion reaction (AHTR). AHTR poses a great risk to patients through kidney function damage in a short time. Previous reports found that heme from destroyed red blood cells impaired kidney function, and NLR family pyrin domain containing 3 (NLRP3) inflammasome was augmented in case of kidney injury. However, the detailed mechanism regarding whether NLRP3 inflammasome is involved in kidney function injury in AHTR is not fully understood yet. Methods Hemolysis models were established by vein injection with human blood plasma or mouse heme from destroyed red blood cells. The injured renal tubular epithelial cells (RTECs) were evaluated by tubular damage markers staining in hemolysis models and in primary RTECs in vitro. The activation of NLRP3 inflammasome in RTECs by hemes was investigated by Western blot, ELISA, scanning electron microscopy, immunofluorescent staining, flow cytometry, and hemolysis models. NLRP3 gene knockout mice were employed to confirm these observations in vitro and in vivo. The binding between a novel inhibitor (66PR) and NLRP3 was affirmed by molecule docking and co‐immunoprecipitation. The rescue of 66PR on kidney function impairment was explored in murine hemolysis models. Results We found that heme could activate NLRP3 inflammasome in RTECs to induce kidney function injury. NLRP3 gene knockout could prevent the damage of RTECs caused by hemes and recover kidney function in AHTR. Moreover, NLRP3 inflammasome chemical inhibitor, 66PR, could bind to NLRP3 protein and inhibit inflammasome activation in RTECs, which consequently relieved the injury of RTECs caused by hemes, and alleviated kidney function damage in the AHTR model. Conclusions Hemes could activate NLRP3 inflammasome in RTECs, and a novel NLRP3 inflammasome inhibitor named 66PR relieved kidney function damage in AHTR. Our findings provided a new possible strategy to treat kidney function failure in AHTR.https://doi.org/10.1002/ctm2.373acute hemolytic transfusion reactionhemeinhibitorNLRP3 inflammasomerenal tubular epithelial cells |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Zhixin Liu Yaozhen Chen Bing Niu Dandan Yin Fan Feng Shunli Gu Qunxing An Jinmei Xu Ning An Jing Zhang Jing Yi Wen Yin Xiangyang Qin Xingbin Hu |
spellingShingle |
Zhixin Liu Yaozhen Chen Bing Niu Dandan Yin Fan Feng Shunli Gu Qunxing An Jinmei Xu Ning An Jing Zhang Jing Yi Wen Yin Xiangyang Qin Xingbin Hu NLRP3 inflammasome of renal tubular epithelial cells induces kidney injury in acute hemolytic transfusion reactions Clinical and Translational Medicine acute hemolytic transfusion reaction heme inhibitor NLRP3 inflammasome renal tubular epithelial cells |
author_facet |
Zhixin Liu Yaozhen Chen Bing Niu Dandan Yin Fan Feng Shunli Gu Qunxing An Jinmei Xu Ning An Jing Zhang Jing Yi Wen Yin Xiangyang Qin Xingbin Hu |
author_sort |
Zhixin Liu |
title |
NLRP3 inflammasome of renal tubular epithelial cells induces kidney injury in acute hemolytic transfusion reactions |
title_short |
NLRP3 inflammasome of renal tubular epithelial cells induces kidney injury in acute hemolytic transfusion reactions |
title_full |
NLRP3 inflammasome of renal tubular epithelial cells induces kidney injury in acute hemolytic transfusion reactions |
title_fullStr |
NLRP3 inflammasome of renal tubular epithelial cells induces kidney injury in acute hemolytic transfusion reactions |
title_full_unstemmed |
NLRP3 inflammasome of renal tubular epithelial cells induces kidney injury in acute hemolytic transfusion reactions |
title_sort |
nlrp3 inflammasome of renal tubular epithelial cells induces kidney injury in acute hemolytic transfusion reactions |
publisher |
Wiley |
series |
Clinical and Translational Medicine |
issn |
2001-1326 |
publishDate |
2021-03-01 |
description |
Abstract Background Blood transfusion, a common basic supporting therapy, can lead to acute hemolytic transfusion reaction (AHTR). AHTR poses a great risk to patients through kidney function damage in a short time. Previous reports found that heme from destroyed red blood cells impaired kidney function, and NLR family pyrin domain containing 3 (NLRP3) inflammasome was augmented in case of kidney injury. However, the detailed mechanism regarding whether NLRP3 inflammasome is involved in kidney function injury in AHTR is not fully understood yet. Methods Hemolysis models were established by vein injection with human blood plasma or mouse heme from destroyed red blood cells. The injured renal tubular epithelial cells (RTECs) were evaluated by tubular damage markers staining in hemolysis models and in primary RTECs in vitro. The activation of NLRP3 inflammasome in RTECs by hemes was investigated by Western blot, ELISA, scanning electron microscopy, immunofluorescent staining, flow cytometry, and hemolysis models. NLRP3 gene knockout mice were employed to confirm these observations in vitro and in vivo. The binding between a novel inhibitor (66PR) and NLRP3 was affirmed by molecule docking and co‐immunoprecipitation. The rescue of 66PR on kidney function impairment was explored in murine hemolysis models. Results We found that heme could activate NLRP3 inflammasome in RTECs to induce kidney function injury. NLRP3 gene knockout could prevent the damage of RTECs caused by hemes and recover kidney function in AHTR. Moreover, NLRP3 inflammasome chemical inhibitor, 66PR, could bind to NLRP3 protein and inhibit inflammasome activation in RTECs, which consequently relieved the injury of RTECs caused by hemes, and alleviated kidney function damage in the AHTR model. Conclusions Hemes could activate NLRP3 inflammasome in RTECs, and a novel NLRP3 inflammasome inhibitor named 66PR relieved kidney function damage in AHTR. Our findings provided a new possible strategy to treat kidney function failure in AHTR. |
topic |
acute hemolytic transfusion reaction heme inhibitor NLRP3 inflammasome renal tubular epithelial cells |
url |
https://doi.org/10.1002/ctm2.373 |
work_keys_str_mv |
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