RIPK3-MLKL-mediated necroinflammation contributes to AKI progression to CKD

Abstract Necroptosis predominates functionally over apoptosis in the pathophysiology of renal ischemia-reperfusion injury (IRI). Inhibition of the core components of the necroptotic pathway—receptor-interacting protein kinase 1 (RIPK1), RIPK3 or mixed lineage kinase domain-like protein (MLKL) reduce...

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Main Authors:	Hui Chen, Yulu Fang, Jianfeng Wu, Hong Chen, Zhenhuan Zou, Xiaohong Zhang, Jing Shao, Yanfang Xu
Format:	Article
Language:	English
Published:	Nature Publishing Group 2018-08-01
Series:	Cell Death and Disease
Online Access:	http://link.springer.com/article/10.1038/s41419-018-0936-8

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recordtype	oai_dc
spelling	doaj-art-602cdd352a6f43d497961d79eed528992018-09-02T11:03:52ZengNature Publishing GroupCell Death and Disease2041-48892018-08-019911510.1038/s41419-018-0936-8RIPK3-MLKL-mediated necroinflammation contributes to AKI progression to CKDHui Chen0Yulu Fang1Jianfeng Wu2Hong Chen3Zhenhuan Zou4Xiaohong Zhang5Jing Shao6Yanfang Xu7Department of Nephrology, First Affiliated Hospital, Fujian Medical UniversityDepartment of Nephrology, First Affiliated Hospital, Fujian Medical UniversitySchool of Life Sciences, Xiamen UniversityDepartment of Pathology, First Affiliated Hospital, Fujian Medical UniversityDepartment of Nephrology, First Affiliated Hospital, Fujian Medical UniversityDepartment of Nephrology, First Affiliated Hospital, Fujian Medical UniversityInstitute for Immunology, Tsinghua University School of MedicineDepartment of Nephrology, First Affiliated Hospital, Fujian Medical UniversityAbstract Necroptosis predominates functionally over apoptosis in the pathophysiology of renal ischemia-reperfusion injury (IRI). Inhibition of the core components of the necroptotic pathway—receptor-interacting protein kinase 1 (RIPK1), RIPK3 or mixed lineage kinase domain-like protein (MLKL) reduced renal injury after ischemia/reperfusion (IR). Necrosis can initiate inflammation, which enhances necrosis in a positive feedback loop, subsequently leading to triggering more inflammation, termed as necroinflammation. However, the mechanisms underlying necroinflammation driven by renal tubular cell necroptosis in progression of AKI to CKD are still largely unknown. Here we showed that the upregulated expression and interactions between RIPK3 and MLKL induced necroptosis of renal proximal tubular cells and contributed to NLRP3 inflammasome activation under the conditions of IRI. Gene deletion of Ripk3 or Mlkl ameliorated renal tubular cell necroptosis, macrophage infiltration and NLRP3 inflammasome activation with a reduction in caspase-1 activation and maturation of IL-1β, and then finally reduced interstitial fibrogenesis in the long term after IRI. Bone marrow chimeras confirmed that RIPK3-MLKL-dependent necroptosis is responsible for the initiation of the early renal injury after IRI, and then necroptosis triggered NLRP3 inflammasome activation, which subsequently accelerates necroptosis and triggers more inflammation in an auto-amplification loop. These data indicate that necroinflammation driven by RIPK3-MLKL-dependent necroptosis plays a crucial role in the progression of IRI to CKD.http://link.springer.com/article/10.1038/s41419-018-0936-8
institution	Open Data Bank
collection	Open Access Journals
building	Directory of Open Access Journals
language	English
format	Article
author	Hui Chen Yulu Fang Jianfeng Wu Hong Chen Zhenhuan Zou Xiaohong Zhang Jing Shao Yanfang Xu
spellingShingle	Hui Chen Yulu Fang Jianfeng Wu Hong Chen Zhenhuan Zou Xiaohong Zhang Jing Shao Yanfang Xu RIPK3-MLKL-mediated necroinflammation contributes to AKI progression to CKD Cell Death and Disease
author_facet	Hui Chen Yulu Fang Jianfeng Wu Hong Chen Zhenhuan Zou Xiaohong Zhang Jing Shao Yanfang Xu
author_sort	Hui Chen
title	RIPK3-MLKL-mediated necroinflammation contributes to AKI progression to CKD
title_short	RIPK3-MLKL-mediated necroinflammation contributes to AKI progression to CKD
title_full	RIPK3-MLKL-mediated necroinflammation contributes to AKI progression to CKD
title_fullStr	RIPK3-MLKL-mediated necroinflammation contributes to AKI progression to CKD
title_full_unstemmed	RIPK3-MLKL-mediated necroinflammation contributes to AKI progression to CKD
title_sort	ripk3-mlkl-mediated necroinflammation contributes to aki progression to ckd
publisher	Nature Publishing Group
series	Cell Death and Disease
issn	2041-4889
publishDate	2018-08-01
description	Abstract Necroptosis predominates functionally over apoptosis in the pathophysiology of renal ischemia-reperfusion injury (IRI). Inhibition of the core components of the necroptotic pathway—receptor-interacting protein kinase 1 (RIPK1), RIPK3 or mixed lineage kinase domain-like protein (MLKL) reduced renal injury after ischemia/reperfusion (IR). Necrosis can initiate inflammation, which enhances necrosis in a positive feedback loop, subsequently leading to triggering more inflammation, termed as necroinflammation. However, the mechanisms underlying necroinflammation driven by renal tubular cell necroptosis in progression of AKI to CKD are still largely unknown. Here we showed that the upregulated expression and interactions between RIPK3 and MLKL induced necroptosis of renal proximal tubular cells and contributed to NLRP3 inflammasome activation under the conditions of IRI. Gene deletion of Ripk3 or Mlkl ameliorated renal tubular cell necroptosis, macrophage infiltration and NLRP3 inflammasome activation with a reduction in caspase-1 activation and maturation of IL-1β, and then finally reduced interstitial fibrogenesis in the long term after IRI. Bone marrow chimeras confirmed that RIPK3-MLKL-dependent necroptosis is responsible for the initiation of the early renal injury after IRI, and then necroptosis triggered NLRP3 inflammasome activation, which subsequently accelerates necroptosis and triggers more inflammation in an auto-amplification loop. These data indicate that necroinflammation driven by RIPK3-MLKL-dependent necroptosis plays a crucial role in the progression of IRI to CKD.
url	http://link.springer.com/article/10.1038/s41419-018-0936-8
_version_	1612647556169334784

RIPK3-MLKL-mediated necroinflammation contributes to AKI progression to CKD

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