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Nucleotide‐Binding Oligomerization Domain‐Like Receptor Protein 3 Deficiency in Vascular Smooth Muscle Cells Prevents Arteriovenous Fistula Failure Despite Chronic Kidney Disease

BACKGROUND: The arteriovenous fistula (AVF) is the preferred hemodialysis access for patients with chronic kidney disease. Chronic kidney disease can increase neointima formation, which greatly contributes to AVF failure by an unknown mechanism. Our study aimed to determine the role of nucleotide‐bi...

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Autores principales: Ding, Xiangchao, Chen, Jiuling, Wu, Chuangyan, Wang, Guohua, Zhou, Cheng, Chen, Shanshan, Wang, Ke, Zhang, Anchen, Ye, Ping, Wu, Jie, Zhang, Hao, Xu, Kaiying, Wang, Sihua, Xia, Jiahong
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405733/
https://www.ncbi.nlm.nih.gov/pubmed/30587058
http://dx.doi.org/10.1161/JAHA.118.011211
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author Ding, Xiangchao
Chen, Jiuling
Wu, Chuangyan
Wang, Guohua
Zhou, Cheng
Chen, Shanshan
Wang, Ke
Zhang, Anchen
Ye, Ping
Wu, Jie
Chen, Shanshan
Zhang, Hao
Xu, Kaiying
Wang, Sihua
Xia, Jiahong
author_facet Ding, Xiangchao
Chen, Jiuling
Wu, Chuangyan
Wang, Guohua
Zhou, Cheng
Chen, Shanshan
Wang, Ke
Zhang, Anchen
Ye, Ping
Wu, Jie
Chen, Shanshan
Zhang, Hao
Xu, Kaiying
Wang, Sihua
Xia, Jiahong
author_sort Ding, Xiangchao
collection PubMed
description BACKGROUND: The arteriovenous fistula (AVF) is the preferred hemodialysis access for patients with chronic kidney disease. Chronic kidney disease can increase neointima formation, which greatly contributes to AVF failure by an unknown mechanism. Our study aimed to determine the role of nucleotide‐binding oligomerization domain‐like receptor protein 3 (NLRP3) in neointima formation induced by experimental AVFs in the presence of chronic kidney disease. METHODS AND RESULTS: From our findings, NLRP3 was upregulated in the intimal lesions of AVFs in both uremic mice and patients. Smooth muscle–specific knockout NLRP3 mice exhibited markedly decreased neointima formation in the outflow vein of AVFs. Compared with primary vascular smooth muscle cells isolated from control mice, those isolated from smooth muscle–specific knockout NLRP3 mice showed compromised proliferation, migration, phenotypic switching, and a weakened ability to activate mononuclear macrophages. To identify how NLRP3 functions, several small‐molecule inhibitors were used. The results showed that NLRP3 regulates smooth muscle cell proliferation and migration through Smad2/3 phosphorylation rather than through caspase‐1/interleukin‐1 signaling. Unexpectedly, the selective NLRP3‐inflammasome inhibitor MCC950 also repressed Smad2/3 phosphorylation and relieved chronic kidney disease–promoted AVF failure independent of macrophages. CONCLUSIONS: Our findings suggest that NLRP3 in vascular smooth muscle cells may play a crucial role in uremia‐associated AVF failure and may be a promising therapeutic target for the treatment of AVF failure.
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spelling pubmed-64057332019-03-21 Nucleotide‐Binding Oligomerization Domain‐Like Receptor Protein 3 Deficiency in Vascular Smooth Muscle Cells Prevents Arteriovenous Fistula Failure Despite Chronic Kidney Disease Ding, Xiangchao Chen, Jiuling Wu, Chuangyan Wang, Guohua Zhou, Cheng Chen, Shanshan Wang, Ke Zhang, Anchen Ye, Ping Wu, Jie Chen, Shanshan Zhang, Hao Xu, Kaiying Wang, Sihua Xia, Jiahong J Am Heart Assoc Original Research BACKGROUND: The arteriovenous fistula (AVF) is the preferred hemodialysis access for patients with chronic kidney disease. Chronic kidney disease can increase neointima formation, which greatly contributes to AVF failure by an unknown mechanism. Our study aimed to determine the role of nucleotide‐binding oligomerization domain‐like receptor protein 3 (NLRP3) in neointima formation induced by experimental AVFs in the presence of chronic kidney disease. METHODS AND RESULTS: From our findings, NLRP3 was upregulated in the intimal lesions of AVFs in both uremic mice and patients. Smooth muscle–specific knockout NLRP3 mice exhibited markedly decreased neointima formation in the outflow vein of AVFs. Compared with primary vascular smooth muscle cells isolated from control mice, those isolated from smooth muscle–specific knockout NLRP3 mice showed compromised proliferation, migration, phenotypic switching, and a weakened ability to activate mononuclear macrophages. To identify how NLRP3 functions, several small‐molecule inhibitors were used. The results showed that NLRP3 regulates smooth muscle cell proliferation and migration through Smad2/3 phosphorylation rather than through caspase‐1/interleukin‐1 signaling. Unexpectedly, the selective NLRP3‐inflammasome inhibitor MCC950 also repressed Smad2/3 phosphorylation and relieved chronic kidney disease–promoted AVF failure independent of macrophages. CONCLUSIONS: Our findings suggest that NLRP3 in vascular smooth muscle cells may play a crucial role in uremia‐associated AVF failure and may be a promising therapeutic target for the treatment of AVF failure. John Wiley and Sons Inc. 2018-12-27 /pmc/articles/PMC6405733/ /pubmed/30587058 http://dx.doi.org/10.1161/JAHA.118.011211 Text en © 2018 The Authors. Published on behalf of the American Heart Association, Inc., by Wiley. This is an open access article under the terms of the http://creativecommons.org/licenses/by-nc/4.0/ License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited and is not used for commercial purposes.
spellingShingle Original Research
Ding, Xiangchao
Chen, Jiuling
Wu, Chuangyan
Wang, Guohua
Zhou, Cheng
Chen, Shanshan
Wang, Ke
Zhang, Anchen
Ye, Ping
Wu, Jie
Chen, Shanshan
Zhang, Hao
Xu, Kaiying
Wang, Sihua
Xia, Jiahong
Nucleotide‐Binding Oligomerization Domain‐Like Receptor Protein 3 Deficiency in Vascular Smooth Muscle Cells Prevents Arteriovenous Fistula Failure Despite Chronic Kidney Disease
title Nucleotide‐Binding Oligomerization Domain‐Like Receptor Protein 3 Deficiency in Vascular Smooth Muscle Cells Prevents Arteriovenous Fistula Failure Despite Chronic Kidney Disease
title_full Nucleotide‐Binding Oligomerization Domain‐Like Receptor Protein 3 Deficiency in Vascular Smooth Muscle Cells Prevents Arteriovenous Fistula Failure Despite Chronic Kidney Disease
title_fullStr Nucleotide‐Binding Oligomerization Domain‐Like Receptor Protein 3 Deficiency in Vascular Smooth Muscle Cells Prevents Arteriovenous Fistula Failure Despite Chronic Kidney Disease
title_full_unstemmed Nucleotide‐Binding Oligomerization Domain‐Like Receptor Protein 3 Deficiency in Vascular Smooth Muscle Cells Prevents Arteriovenous Fistula Failure Despite Chronic Kidney Disease
title_short Nucleotide‐Binding Oligomerization Domain‐Like Receptor Protein 3 Deficiency in Vascular Smooth Muscle Cells Prevents Arteriovenous Fistula Failure Despite Chronic Kidney Disease
title_sort nucleotide‐binding oligomerization domain‐like receptor protein 3 deficiency in vascular smooth muscle cells prevents arteriovenous fistula failure despite chronic kidney disease
topic Original Research
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6405733/
https://www.ncbi.nlm.nih.gov/pubmed/30587058
http://dx.doi.org/10.1161/JAHA.118.011211
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