Trimethylamine-N-Oxide Aggravates Kidney Injury via Activation of p38/MAPK Signaling and Upregulation of HuR

Background: Trimethylamine-N-oxide (TMAO) is an intestinal metabolic toxin, which is produced by gut flora via metabolizing high-choline foods. TMAO is known to increase the risk of atherosclerosis and cardiovascular events in chronic kidney disease (CKD) patients. Objectives: The objective of this...

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Autores principales:	Yunshi Lai, Haie Tang, Xinrong Zhang, Zhanmei Zhou, Miaomiao Zhou, Zheng Hu, Fengxin Zhu, Lei Zhang, Jing Nie
Formato:	article
Lenguaje:	EN
Publicado:	Karger Publishers 2021
Materias:	trimethylamine-n-oxide inflammatory injury p38/mapk pathway human antigen r chronic kidney disease Dermatology RL1-803 Diseases of the circulatory (Cardiovascular) system RC666-701 Diseases of the genitourinary system. Urology RC870-923
Acceso en línea:	https://doaj.org/article/adaae32e43ac43308ea3ab58749d9180
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spelling	oai:doaj.org-article:adaae32e43ac43308ea3ab58749d91802021-12-02T12:40:22ZTrimethylamine-N-Oxide Aggravates Kidney Injury via Activation of p38/MAPK Signaling and Upregulation of HuR1420-40961423-014310.1159/000519603https://doaj.org/article/adaae32e43ac43308ea3ab58749d91802021-11-01T00:00:00Zhttps://www.karger.com/Article/FullText/519603https://doaj.org/toc/1420-4096https://doaj.org/toc/1423-0143Background: Trimethylamine-N-oxide (TMAO) is an intestinal metabolic toxin, which is produced by gut flora via metabolizing high-choline foods. TMAO is known to increase the risk of atherosclerosis and cardiovascular events in chronic kidney disease (CKD) patients. Objectives: The objective of this study was to explore the role and mechanism of TMAO aggravating kidney injury. Method: We used the five-sixths nephrectomy (5/6 Nx)-induced CKD rats to investigate whether TMAO could aggravate kidney damage and its possible mechanisms. Six weeks after the operation, the two groups of 5/6 Nx rats were subjected to intraperitoneal injection with 2.5% glucose peritoneal dialysis fluid (2.5% PDF) and 2.5% PDF plus TMAO 20 mg/kg/day. Results: In this study, we provided evidence showing TMAO significantly aggravated renal failure as well as inflammatory cell infiltration and in five-sixths nephrectomy-induced CKD rats. We found that TMAO could upregulate inflammatory factors including MCP-1, TNF-α, IL-6, IL-1β, and IL-18 by activating p38 phosphorylation and upregulation of human antigen R. TMAO could aggravate oxidative stress by upregulating NOX4 and downregulating SOD. The result also confirmed that TMAO promoted NLRP3 inflammasome formation as well as cleaved caspase-1 and IL-1β activation in the kidney tissue. Conclusions: Taken together, the present study validates TMAO as a pro-inflammatory factor that causes renal inflammatory injury and renal function impairment. Inhibition of TMAO synthesis or promoting its clearance may be a potential therapeutic approach of CKD in the future.Yunshi LaiHaie TangXinrong ZhangZhanmei ZhouMiaomiao ZhouZheng HuFengxin ZhuLei ZhangJing NieKarger Publishersarticletrimethylamine-n-oxideinflammatory injuryp38/mapk pathwayhuman antigen rchronic kidney diseaseDermatologyRL1-803Diseases of the circulatory (Cardiovascular) systemRC666-701Diseases of the genitourinary system. UrologyRC870-923ENKidney & Blood Pressure Research, Pp 1-11 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	trimethylamine-n-oxide inflammatory injury p38/mapk pathway human antigen r chronic kidney disease Dermatology RL1-803 Diseases of the circulatory (Cardiovascular) system RC666-701 Diseases of the genitourinary system. Urology RC870-923
spellingShingle	trimethylamine-n-oxide inflammatory injury p38/mapk pathway human antigen r chronic kidney disease Dermatology RL1-803 Diseases of the circulatory (Cardiovascular) system RC666-701 Diseases of the genitourinary system. Urology RC870-923 Yunshi Lai Haie Tang Xinrong Zhang Zhanmei Zhou Miaomiao Zhou Zheng Hu Fengxin Zhu Lei Zhang Jing Nie Trimethylamine-N-Oxide Aggravates Kidney Injury via Activation of p38/MAPK Signaling and Upregulation of HuR
description	Background: Trimethylamine-N-oxide (TMAO) is an intestinal metabolic toxin, which is produced by gut flora via metabolizing high-choline foods. TMAO is known to increase the risk of atherosclerosis and cardiovascular events in chronic kidney disease (CKD) patients. Objectives: The objective of this study was to explore the role and mechanism of TMAO aggravating kidney injury. Method: We used the five-sixths nephrectomy (5/6 Nx)-induced CKD rats to investigate whether TMAO could aggravate kidney damage and its possible mechanisms. Six weeks after the operation, the two groups of 5/6 Nx rats were subjected to intraperitoneal injection with 2.5% glucose peritoneal dialysis fluid (2.5% PDF) and 2.5% PDF plus TMAO 20 mg/kg/day. Results: In this study, we provided evidence showing TMAO significantly aggravated renal failure as well as inflammatory cell infiltration and in five-sixths nephrectomy-induced CKD rats. We found that TMAO could upregulate inflammatory factors including MCP-1, TNF-α, IL-6, IL-1β, and IL-18 by activating p38 phosphorylation and upregulation of human antigen R. TMAO could aggravate oxidative stress by upregulating NOX4 and downregulating SOD. The result also confirmed that TMAO promoted NLRP3 inflammasome formation as well as cleaved caspase-1 and IL-1β activation in the kidney tissue. Conclusions: Taken together, the present study validates TMAO as a pro-inflammatory factor that causes renal inflammatory injury and renal function impairment. Inhibition of TMAO synthesis or promoting its clearance may be a potential therapeutic approach of CKD in the future.
format	article
author	Yunshi Lai Haie Tang Xinrong Zhang Zhanmei Zhou Miaomiao Zhou Zheng Hu Fengxin Zhu Lei Zhang Jing Nie
author_facet	Yunshi Lai Haie Tang Xinrong Zhang Zhanmei Zhou Miaomiao Zhou Zheng Hu Fengxin Zhu Lei Zhang Jing Nie
author_sort	Yunshi Lai
title	Trimethylamine-N-Oxide Aggravates Kidney Injury via Activation of p38/MAPK Signaling and Upregulation of HuR
title_short	Trimethylamine-N-Oxide Aggravates Kidney Injury via Activation of p38/MAPK Signaling and Upregulation of HuR
title_full	Trimethylamine-N-Oxide Aggravates Kidney Injury via Activation of p38/MAPK Signaling and Upregulation of HuR
title_fullStr	Trimethylamine-N-Oxide Aggravates Kidney Injury via Activation of p38/MAPK Signaling and Upregulation of HuR
title_full_unstemmed	Trimethylamine-N-Oxide Aggravates Kidney Injury via Activation of p38/MAPK Signaling and Upregulation of HuR
title_sort	trimethylamine-n-oxide aggravates kidney injury via activation of p38/mapk signaling and upregulation of hur
publisher	Karger Publishers
publishDate	2021
url	https://doaj.org/article/adaae32e43ac43308ea3ab58749d9180
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_version_	1718393759215910912

Trimethylamine-N-Oxide Aggravates Kidney Injury via Activation of p38/MAPK Signaling and Upregulation of HuR

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