Metabolic rewiring and epigenetic reprogramming in leptin receptor-deficient db/db diabetic nephropathy mice.
DNA methylation
Diabetic nephropathy
Epigenetics
Gene expression
Metabolomic
TCA cycle
Journal
European journal of pharmacology
ISSN: 1879-0712
Titre abrégé: Eur J Pharmacol
Pays: Netherlands
ID NLM: 1254354
Informations de publication
Date de publication:
15 Aug 2023
15 Aug 2023
Historique:
received:
28
07
2022
revised:
14
06
2023
accepted:
15
06
2023
medline:
30
6
2023
pubmed:
19
6
2023
entrez:
18
6
2023
Statut:
ppublish
Résumé
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the United States. Emerging evidence suggests that mitochondrial metabolism and epigenetics play an important role in the development and progression of DN and its complications. For the first time, we investigated the regulation of cellular metabolism, DNA methylation, and transcriptome status by high glucose (HG) in the kidney of leptin receptor-deficient db/db mice using multi-omics approaches. The metabolomics was performed by liquid-chromatography-mass spectrometry (LC-MS), while epigenomic CpG methylation coupled with transcriptomic gene expression was analyzed by next-generation sequencing. LC-MS analysis of glomerular and cortex tissue samples of db/db mice showed that HG regulated several cellular metabolites and metabolism-related signaling pathways, including S-adenosylmethionine, S-adenosylhomocysteine, methionine, glutamine, and glutamate. Gene expression study by RNA-seq analysis suggests transforming growth factor beta 1 (TGFβ1) and pro-inflammatory pathways play important roles in early DN. Epigenomic CpG methyl-seq showed HG revoked a list of differentially methylated regions in the promoter region of the genes. Integrated analysis of DNA methylation in the promoter regions of genes and gene expression changes across time points identified several genes persistently altered in DNA methylation and gene expression. Cyp2d22, Slc1a4, and Ddah1 are some identified genes that could reflect dysregulated genes involved in renal function and DN. Our results suggest that leptin receptor deficiency leading to HG regulates metabolic rewiring, including SAM potentially driving DNA methylation and transcriptomic signaling that could be involved in the progression of DN.
Sections du résumé
BACKGROUND
BACKGROUND
Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the United States. Emerging evidence suggests that mitochondrial metabolism and epigenetics play an important role in the development and progression of DN and its complications. For the first time, we investigated the regulation of cellular metabolism, DNA methylation, and transcriptome status by high glucose (HG) in the kidney of leptin receptor-deficient db/db mice using multi-omics approaches.
METHODS
METHODS
The metabolomics was performed by liquid-chromatography-mass spectrometry (LC-MS), while epigenomic CpG methylation coupled with transcriptomic gene expression was analyzed by next-generation sequencing.
RESULTS
RESULTS
LC-MS analysis of glomerular and cortex tissue samples of db/db mice showed that HG regulated several cellular metabolites and metabolism-related signaling pathways, including S-adenosylmethionine, S-adenosylhomocysteine, methionine, glutamine, and glutamate. Gene expression study by RNA-seq analysis suggests transforming growth factor beta 1 (TGFβ1) and pro-inflammatory pathways play important roles in early DN. Epigenomic CpG methyl-seq showed HG revoked a list of differentially methylated regions in the promoter region of the genes. Integrated analysis of DNA methylation in the promoter regions of genes and gene expression changes across time points identified several genes persistently altered in DNA methylation and gene expression. Cyp2d22, Slc1a4, and Ddah1 are some identified genes that could reflect dysregulated genes involved in renal function and DN.
CONCLUSION
CONCLUSIONS
Our results suggest that leptin receptor deficiency leading to HG regulates metabolic rewiring, including SAM potentially driving DNA methylation and transcriptomic signaling that could be involved in the progression of DN.
Identifiants
pubmed: 37331680
pii: S0014-2999(23)00377-1
doi: 10.1016/j.ejphar.2023.175866
pii:
doi:
Substances chimiques
Receptors, Leptin
0
leptin receptor, mouse
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
175866Informations de copyright
Copyright © 2023. Published by Elsevier B.V.
Déclaration de conflit d'intérêts
Declaration of competing interest The authors declare no conflict of interest.