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Glycine N-methyltransferase inhibits aristolochic acid nephropathy by increasing CYP3A44 and decreasing NQO1 expression in female mouse hepatocytes
- Source :
- Scientific Reports, Scientific Reports, Vol 8, Iss 1, Pp 1-17 (2018)
- Publication Year :
- 2018
- Publisher :
- Nature Publishing Group UK, 2018.
-
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.
- Subjects :
- 0301 basic medicine
Male
Transcriptional Activation
medicine.medical_specialty
Science
Down-Regulation
Glycine N-Methyltransferase
Article
Nephropathy
03 medical and health sciences
Mice
Sex Factors
Downregulation and upregulation
Cytochrome P-450 Enzyme System
Internal medicine
medicine
NAD(P)H Dehydrogenase (Quinone)
Animals
Mice, Knockout
Pregnane X receptor
Multidisciplinary
Chemistry
Promoter
Protective Factors
medicine.disease
Glycine N-methyltransferase
Up-Regulation
Mice, Inbred C57BL
030104 developmental biology
Endocrinology
GNMT
Knockout mouse
Hepatocytes
Medicine
Aristolochic Acids
Female
Kidney Diseases
Drug metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 20452322
- Volume :
- 8
- Database :
- OpenAIRE
- Journal :
- Scientific Reports
- Accession number :
- edsair.doi.dedup.....84c4fff5420c155fc792b97a0afeb002