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Homoarginine- and Creatine-Dependent Gene Regulation in Murine Brains with l -Arginine:Glycine Amidinotransferase Deficiency

Authors
  • Jensen, Märit1, 2
  • Müller, Christian1,
  • Schwedhelm, Edzard3
  • Arunachalam, Priyadharshini2
  • Gelderblom, Mathias2
  • Magnus, Tim2
  • Gerloff, Christian2
  • Zeller, Tanja1,
  • Choe, Chi-un2
  • 1 (T.Z.)
  • 2 (C.G.)
  • 3 Institute of Clinical Pharmacology and Toxicology, University Medical Centre Hamburg-Eppendorf, 20246 Hamburg, Germany
Type
Published Article
Journal
International Journal of Molecular Sciences
Publisher
MDPI AG
Publication Date
Mar 09, 2020
Volume
21
Issue
5
Identifiers
DOI: 10.3390/ijms21051865
PMID: 32182846
PMCID: PMC7084559
Source
PubMed Central
Keywords
License
Green

Abstract

l -arginine:glycine amidinotransferase (AGAT) and its metabolites homoarginine (hArg) and creatine have been linked to stroke pathology in both human and mouse studies. However, a comprehensive understanding of the underlying molecular mechanism is lacking. To investigate transcriptional changes in cerebral AGAT metabolism, we applied a transcriptome analysis in brains of wild-type (WT) mice compared to untreated AGAT-deficient (AGAT−/−) mice and AGAT−/− mice with creatine or hArg supplementation. We identified significantly regulated genes between AGAT−/− and WT mice in two independent cohorts of mice which can be linked to amino acid metabolism ( Ivd , Lcmt2 ), creatine metabolism ( Slc6a8 ), cerebral myelination ( Bcas1 ) and neuronal excitability ( Kcnip3 ). While Ivd and Kcnip3 showed regulation by hArg supplementation, Bcas1 and Slc6a8 were creatine dependent. Additional regulated genes such as Pla2g4e and Exd1 need further evaluation of their influence on cerebral function. Experimental stroke models showed a significant regulation of Bcas1 and Slc6a8 . Together, these results reveal that AGAT deficiency, hArg and creatine regulate gene expression in the brain, which may be critical in stroke pathology.

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