Glycine N-methyltransferase inhibits aristolochic acid nephropathy by increasing CYP3A44 and decreasing NQO1 expression in female mouse hepatocytes

Abstract Plants containing aristolochic acids (AA) are nephrotoxins. Glycine N-methyltransferase (GNMT) acts to bind environmental toxins such as benzo(a)pyrene and aflatoxin B1, translocate into nucleus, and alter hepatic metabolism. This study aims to determine the role of GNMT in AA-induced nephr...

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Autores principales:	Ming-Min Chang, Chang-Ni Lin, Cheng-Chieh Fang, Marcelo Chen, Peir-In Liang, Wei-Ming Li, Bi-Wen Yeh, Hung-Chi Cheng, Bu-Miin Huang, Wen-Jeng Wu, Yi-Ming Arthur Chen
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e6f8223a179649068752491c14228b5c
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spelling	oai:doaj.org-article:e6f8223a179649068752491c14228b5c2021-12-02T11:40:46ZGlycine N-methyltransferase inhibits aristolochic acid nephropathy by increasing CYP3A44 and decreasing NQO1 expression in female mouse hepatocytes10.1038/s41598-018-22298-62045-2322https://doaj.org/article/e6f8223a179649068752491c14228b5c2018-05-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-22298-6https://doaj.org/toc/2045-2322Abstract Plants containing aristolochic acids (AA) are nephrotoxins. Glycine N-methyltransferase (GNMT) acts to bind environmental toxins such as benzo(a)pyrene and aflatoxin B1, translocate into nucleus, and alter hepatic metabolism. This study aims to determine the role of GNMT in AA-induced nephropathy. We established an AA nephropathy mouse model and found that AA type I (AAI)-induced nephropathy at a lower concentration in male than in female mice, implying sex differences in AAI resistance. Microarray analysis and AAI-treated mouse models showed that GNMT moderately reduced AAI-induced nephropathy by lowering the upregulated level of NQO1 in male, but significantly improved the nephropathy additionally by increasing Cyp3A44/3A41 in female. The protective effects of GNMT were absent in female GNMT knockout mice, in which re-expression of hepatic GNMT significantly decreased AAI-induced nephropathy. Mechanism-wise, AAI enhanced GNMT nuclear translocation, resulting in GNMT interaction with the promoter region of the genes encoding Nrf2 and CAR/PXR, the transcription factors for NQO1 and CYP3A44/3A41, respectively. Unlike the preference for Nrf2/NQO1 transcriptions at lower levels of GNMT, overexpression of GNMT preferred CAR/PXR/CYP3A44/3A41 transcriptions and alleviated kidney injury upon AAI treatment. In summary, hepatic GNMT protected mice from AAI nephropathy by enhancing CAR/PXR/CYP3A44/3A41 transcriptions and reducing Nrf2/NQO1 transcriptions.Ming-Min ChangChang-Ni LinCheng-Chieh FangMarcelo ChenPeir-In LiangWei-Ming LiBi-Wen YehHung-Chi ChengBu-Miin HuangWen-Jeng WuYi-Ming Arthur ChenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-17 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Ming-Min Chang Chang-Ni Lin Cheng-Chieh Fang Marcelo Chen Peir-In Liang Wei-Ming Li Bi-Wen Yeh Hung-Chi Cheng Bu-Miin Huang Wen-Jeng Wu Yi-Ming Arthur Chen Glycine N-methyltransferase inhibits aristolochic acid nephropathy by increasing CYP3A44 and decreasing NQO1 expression in female mouse hepatocytes
description	Abstract Plants containing aristolochic acids (AA) are nephrotoxins. Glycine N-methyltransferase (GNMT) acts to bind environmental toxins such as benzo(a)pyrene and aflatoxin B1, translocate into nucleus, and alter hepatic metabolism. This study aims to determine the role of GNMT in AA-induced nephropathy. We established an AA nephropathy mouse model and found that AA type I (AAI)-induced nephropathy at a lower concentration in male than in female mice, implying sex differences in AAI resistance. Microarray analysis and AAI-treated mouse models showed that GNMT moderately reduced AAI-induced nephropathy by lowering the upregulated level of NQO1 in male, but significantly improved the nephropathy additionally by increasing Cyp3A44/3A41 in female. The protective effects of GNMT were absent in female GNMT knockout mice, in which re-expression of hepatic GNMT significantly decreased AAI-induced nephropathy. Mechanism-wise, AAI enhanced GNMT nuclear translocation, resulting in GNMT interaction with the promoter region of the genes encoding Nrf2 and CAR/PXR, the transcription factors for NQO1 and CYP3A44/3A41, respectively. Unlike the preference for Nrf2/NQO1 transcriptions at lower levels of GNMT, overexpression of GNMT preferred CAR/PXR/CYP3A44/3A41 transcriptions and alleviated kidney injury upon AAI treatment. In summary, hepatic GNMT protected mice from AAI nephropathy by enhancing CAR/PXR/CYP3A44/3A41 transcriptions and reducing Nrf2/NQO1 transcriptions.
format	article
author	Ming-Min Chang Chang-Ni Lin Cheng-Chieh Fang Marcelo Chen Peir-In Liang Wei-Ming Li Bi-Wen Yeh Hung-Chi Cheng Bu-Miin Huang Wen-Jeng Wu Yi-Ming Arthur Chen
author_facet	Ming-Min Chang Chang-Ni Lin Cheng-Chieh Fang Marcelo Chen Peir-In Liang Wei-Ming Li Bi-Wen Yeh Hung-Chi Cheng Bu-Miin Huang Wen-Jeng Wu Yi-Ming Arthur Chen
author_sort	Ming-Min Chang
title	Glycine N-methyltransferase inhibits aristolochic acid nephropathy by increasing CYP3A44 and decreasing NQO1 expression in female mouse hepatocytes
title_short	Glycine N-methyltransferase inhibits aristolochic acid nephropathy by increasing CYP3A44 and decreasing NQO1 expression in female mouse hepatocytes
title_full	Glycine N-methyltransferase inhibits aristolochic acid nephropathy by increasing CYP3A44 and decreasing NQO1 expression in female mouse hepatocytes
title_fullStr	Glycine N-methyltransferase inhibits aristolochic acid nephropathy by increasing CYP3A44 and decreasing NQO1 expression in female mouse hepatocytes
title_full_unstemmed	Glycine N-methyltransferase inhibits aristolochic acid nephropathy by increasing CYP3A44 and decreasing NQO1 expression in female mouse hepatocytes
title_sort	glycine n-methyltransferase inhibits aristolochic acid nephropathy by increasing cyp3a44 and decreasing nqo1 expression in female mouse hepatocytes
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/e6f8223a179649068752491c14228b5c
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Glycine N-methyltransferase inhibits aristolochic acid nephropathy by increasing CYP3A44 and decreasing NQO1 expression in female mouse hepatocytes

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