The Fibrotic Effects of TMAO on Human Renal Fibroblasts Is Mediated by NLRP3, Caspase-1 and the PERK/Akt/mTOR Pathway

Trimethylamine N-oxide (TMAO), a product of gut microbiota metabolism, has previously been shown to be implicated in chronic kidney disease. A high TMAO-containing diet has been found to cause tubulointerstitial renal fibrosis in mice. However, today there are no data linking specific molecular path...

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Autores principales:	Stefania Kapetanaki, Ashok Kumar Kumawat, Katarina Persson, Isak Demirel
Formato:	article
Lenguaje:	EN
Publicado:	MDPI AG 2021
Materias:	TMAO renal fibroblasts proliferation collagen chronic kidney disease Biology (General) QH301-705.5 Chemistry QD1-999
Acceso en línea:	https://doaj.org/article/4646131ea33b4104840acc616bfab10c
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spelling	oai:doaj.org-article:4646131ea33b4104840acc616bfab10c2021-11-11T17:17:13ZThe Fibrotic Effects of TMAO on Human Renal Fibroblasts Is Mediated by NLRP3, Caspase-1 and the PERK/Akt/mTOR Pathway10.3390/ijms2221118641422-00671661-6596https://doaj.org/article/4646131ea33b4104840acc616bfab10c2021-11-01T00:00:00Zhttps://www.mdpi.com/1422-0067/22/21/11864https://doaj.org/toc/1661-6596https://doaj.org/toc/1422-0067Trimethylamine N-oxide (TMAO), a product of gut microbiota metabolism, has previously been shown to be implicated in chronic kidney disease. A high TMAO-containing diet has been found to cause tubulointerstitial renal fibrosis in mice. However, today there are no data linking specific molecular pathways with the effect of TMAO on human renal fibrosis. The aim of this study was to investigate the fibrotic effects of TMAO on renal fibroblasts and to elucidate the molecular pathways involved. We found that TMAO promoted renal fibroblast activation and fibroblast proliferation via the PERK/Akt/mTOR pathway, NLRP3, and caspase-1 signaling. We also found that TMAO increased the total collagen production from renal fibroblasts via the PERK/Akt/mTOR pathway. However, TMAO did not induce fibronectin or TGF-β1 release from renal fibroblasts. We have unraveled that the PERK/Akt/mTOR pathway, NLRP3, and caspase-1 mediates TMAO’s fibrotic effect on human renal fibroblasts. Our results can pave the way for future research to further clarify the molecular mechanism behind TMAO’s effects and to identify novel therapeutic targets in the context of chronic kidney disease.Stefania KapetanakiAshok Kumar KumawatKatarina PerssonIsak DemirelMDPI AGarticleTMAOrenal fibroblastsproliferationcollagenchronic kidney diseaseBiology (General)QH301-705.5ChemistryQD1-999ENInternational Journal of Molecular Sciences, Vol 22, Iss 11864, p 11864 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	TMAO renal fibroblasts proliferation collagen chronic kidney disease Biology (General) QH301-705.5 Chemistry QD1-999
spellingShingle	TMAO renal fibroblasts proliferation collagen chronic kidney disease Biology (General) QH301-705.5 Chemistry QD1-999 Stefania Kapetanaki Ashok Kumar Kumawat Katarina Persson Isak Demirel The Fibrotic Effects of TMAO on Human Renal Fibroblasts Is Mediated by NLRP3, Caspase-1 and the PERK/Akt/mTOR Pathway
description	Trimethylamine N-oxide (TMAO), a product of gut microbiota metabolism, has previously been shown to be implicated in chronic kidney disease. A high TMAO-containing diet has been found to cause tubulointerstitial renal fibrosis in mice. However, today there are no data linking specific molecular pathways with the effect of TMAO on human renal fibrosis. The aim of this study was to investigate the fibrotic effects of TMAO on renal fibroblasts and to elucidate the molecular pathways involved. We found that TMAO promoted renal fibroblast activation and fibroblast proliferation via the PERK/Akt/mTOR pathway, NLRP3, and caspase-1 signaling. We also found that TMAO increased the total collagen production from renal fibroblasts via the PERK/Akt/mTOR pathway. However, TMAO did not induce fibronectin or TGF-β1 release from renal fibroblasts. We have unraveled that the PERK/Akt/mTOR pathway, NLRP3, and caspase-1 mediates TMAO’s fibrotic effect on human renal fibroblasts. Our results can pave the way for future research to further clarify the molecular mechanism behind TMAO’s effects and to identify novel therapeutic targets in the context of chronic kidney disease.
format	article
author	Stefania Kapetanaki Ashok Kumar Kumawat Katarina Persson Isak Demirel
author_facet	Stefania Kapetanaki Ashok Kumar Kumawat Katarina Persson Isak Demirel
author_sort	Stefania Kapetanaki
title	The Fibrotic Effects of TMAO on Human Renal Fibroblasts Is Mediated by NLRP3, Caspase-1 and the PERK/Akt/mTOR Pathway
title_short	The Fibrotic Effects of TMAO on Human Renal Fibroblasts Is Mediated by NLRP3, Caspase-1 and the PERK/Akt/mTOR Pathway
title_full	The Fibrotic Effects of TMAO on Human Renal Fibroblasts Is Mediated by NLRP3, Caspase-1 and the PERK/Akt/mTOR Pathway
title_fullStr	The Fibrotic Effects of TMAO on Human Renal Fibroblasts Is Mediated by NLRP3, Caspase-1 and the PERK/Akt/mTOR Pathway
title_full_unstemmed	The Fibrotic Effects of TMAO on Human Renal Fibroblasts Is Mediated by NLRP3, Caspase-1 and the PERK/Akt/mTOR Pathway
title_sort	fibrotic effects of tmao on human renal fibroblasts is mediated by nlrp3, caspase-1 and the perk/akt/mtor pathway
publisher	MDPI AG
publishDate	2021
url	https://doaj.org/article/4646131ea33b4104840acc616bfab10c
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The Fibrotic Effects of TMAO on Human Renal Fibroblasts Is Mediated by NLRP3, Caspase-1 and the PERK/Akt/mTOR Pathway

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