Mediterranean G6PD variant rats are protected from Angiotensin II-induced hypertension and kidney damage, but not from inflammation and arterial stiffness

Matsumura, Shun; D'Addiaro, Catherine; Slivano, Orazio J.; Miguel, Carmen De; Stier, Charles T.; Gupte, Rakhee; Miano, Joseph M.; Gupte, Sachin A.

doi:10.1016/j.vph.2022.107002

Cited by 3 publications

(3 citation statements)

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“…Here, we demonstrate that the G6PD S188F loss-of-function mutation led to augmented TET2 and TET3 expression and, in turn, hypomethylation, which activated the transcription of the SMC differentiation gene program, as well as hypermethylation, which repressed genes associated with cell inflammation and proliferation in vascular tissue. This presumably prevents the transitioning of SMCs from a healthy to a disease state and perhaps reduces susceptibility to vascular diseases such as hypertension, large artery stiffness, and intimal hyperplasia in G6PD S188F rats [16,50].…”

Section: Discussionmentioning

confidence: 99%

G6PD Orchestrates Genome-Wide DNA Methylation and Gene Expression in the Vascular Wall

Signoretti,

Gupte

2023

IJMS

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Recent advances have revealed the importance of epigenetic modifications to gene regulation and transcriptional activity. DNA methylation, a determinant of genetic imprinting and the de novo silencing of genes genome-wide, is known to be controlled by DNA methyltransferases (DNMT) and demethylases (TET) under disease conditions. However, the mechanism(s)/factor(s) influencing the expression and activity of epigenetic writers and erasers, and thus DNA methylation, in healthy vascular tissue is incompletely understood. Based on our recent studies, we hypothesized that glucose-6-phosphate dehydrogenase (G6PD) is a modifier of DNMT and TET expression and activity and an enabler of gene expression. In the aorta of CRISPR-edited rats with the Mediterranean G6PD variant, we determined DNA methylation by whole-genome bisulfite sequencing, gene expression by RNA sequencing, and large artery stiffness by echocardiography. Here, we documented higher expression of Dnmt1, Dnmt3a, Tet2, and Tet3 in aortas from Mediterranean G6PDS188F variant (a loss-of-function single nucleotide polymorphism) rats than their wild-type littermates. Concomitantly, we identified 17,618 differentially methylated loci genome-wide (5787 hypermethylated loci, including down-regulated genes encoding inflammation- and vasoconstriction-causing proteins, and 11,827 hypomethylated loci, including up-regulated genes encoding smooth muscle cell differentiation- and fatty acid metabolism-promoting proteins) in aortas from G6PDS188F as compared to wild-type rats. Our results demonstrated that nitric oxide, which is generated in a G6PD-derived NADPH-dependent manner, increases TET and decreases DNMT activity. Further, we observed less large artery (aorta) stiffness in G6PDS188F as compared to wild-type rats. These results establish a noncanonical function of the wild-type G6PD and G6PDS188F variant in the regulation of DNA methylation and gene expression in healthy vascular tissue and reveal that the G6PDS188F variant contributes to reducing large artery stiffness.

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Section: Discussionmentioning

confidence: 99%

G6PD Orchestrates Genome-Wide DNA Methylation and Gene Expression in the Vascular Wall

Signoretti,

Gupte

2023

IJMS

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“…These findings imply that renal vascular obstruction may be a critical factor in the development of renal injury. The renin-AngII system can cause microvascular damage and accelerate the progression of acute tubular necrosis and cortical necrosis, potentially leading to irreversible renal failure ( 90 , 91 ).…”

Section: Discussionmentioning

confidence: 99%

Bioinformatics analysis of potential pathogenesis and risk genes of immunoinflammation-promoted renal injury in severe COVID-19

Chen

et al. 2022

Front. Immunol.

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Renal injury secondary to COVID-19 is an important factor for the poor prognosis of COVID-19 patients. The pathogenesis of renal injury caused by aberrant immune inflammatory of COVID-19 remains unclear. In this study, a total of 166 samples from 4 peripheral blood transcriptomic datasets of COVID-19 patients were integrated. By using the weighted gene co-expression network (WGCNA) algorithm, we identified key genes for mild, moderate, and severe COVID-19. Subsequently, taking these genes as input genes, we performed Short Time-series Expression Miner (STEM) analysis in a time consecutive ischemia-reperfusion injury (IRI) -kidney dataset to identify genes associated with renal injury in COVID-19. The results showed that only in severe COVID-19 there exist a small group of genes associated with the progression of renal injury. Gene enrichment analysis revealed that these genes are involved in extensive immune inflammation and cell death-related pathways. A further protein-protein interaction (PPI) network analysis screened 15 PPI-hub genes: ALOX5, CD38, GSF3R, LGR, RPR1, HCK, ITGAX, LYN, MAPK3, NCF4, SELP, SPI1, WAS, TLR2 and TLR4. Single-cell sequencing analysis indicated that PPI-hub genes were mainly distributed in neutrophils, macrophages, and dendritic cells. Intercellular ligand-receptor analysis characterized the activated ligand-receptors between these immune cells and parenchyma cells in depth. And KEGG enrichment analysis revealed that viral protein interaction with cytokine and cytokine receptor, necroptosis, and Toll-like receptor signaling pathway may be potentially essential for immune cell infiltration leading to COVID-19 renal injury. Finally, we validated the expression pattern of PPI-hub genes in an independent data set by random forest. In addition, we found that the high expression of these genes was correlated with a low glomerular filtration rate. Including them as risk genes in lasso regression, we constructed a Nomogram model for predicting severe COVID-19. In conclusion, our study explores the pathogenesis of renal injury promoted by immunoinflammatory in severe COVID-19 and extends the clinical utility of its key genes.

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“…Here, we demonstrate that the G6PD S188F loss-of-function mutation led to augmented TET2 and TET3 expression and, in turn, hypomethylation that activated transcription of the SMC differentiation gene program as well as hypermethylation that repressed genes associated with cell inflammation and proliferation in vascular tissue. This presumably prevents transitioning of SMCs from a healthy to a disease state and reduces hypertension, large artery stiffness, and intimal hyperplasia in G6PD S188F rats 16,52 .…”

Section: Dnmt-catalyzed Methylation Of Cytosine Within Cpg Islands In...mentioning

confidence: 99%

Studies in CRISPR-generated Mediterranean G6PD variant rats reveal G6PD orchestrates genome-wide DNA methylation and gene expression in vascular wall

Signoretti

Gupte

2023

Preprint

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Background: Recent advances have revealed the importance of epigenetic modifications to gene regulation and transcriptional activity. DNA methylation, a determinant of genetic imprinting and de novo silencing of genes genome-wide, is known to be controlled by DNA methyltransferases (DNMT) and demethylases (TET) under disease conditions. However, the mechanism(s)/factor(s) influencing the expression and activity of DNMTs and TETs, and thus DNA methylation, in healthy vascular tissue is incompletely understood. Based on our recent studies, we hypothesized that glucose-6-phosphate dehydrogenase (G6PD) is a modifier of DNMT and TET expression and activity and an enabler of gene expression. Methods: In aorta of CRISPR-edited rats with the Mediterranean G6PD variant we determined DNA methylation by whole-genome bisulfite sequencing, gene expression by RNA sequencing, and large artery stiffness by echocardiography. Results: Here, we documented higher expression of Dnmt3a, Tet2, and Tet3 in aortas from Mediterranean G6PDS188F variant (a loss-of-function single nucleotide polymorphism) rats than their wild-type littermates. Concomitantly, we identified 17,618 differentially methylated loci genome-wide (5,787 hypermethylated loci, including down-regulated genes encoding inflammation- and vasoconstriction-causing proteins, and 11,827 hypomethylated loci, including up-regulated genes encoding smooth muscle cell differentiation- and fatty acid metabolism-promoting proteins) in aorta from G6PDS188F as compared to wild-type rats. Further, we observed less large artery (aorta) stiffness in G6PDS188F as compared to wild-type rats. Conclusions: These results establish a noncanonical function of the wild-type G6PD and G6PDS188F variant in the regulation of DNA methylation and gene expression in healthy vascular tissue and reveals G6PDS188F variant contributes to reduce large artery stiffness.

show abstract

Mediterranean G6PD variant rats are protected from Angiotensin II-induced hypertension and kidney damage, but not from inflammation and arterial stiffness

Cited by 3 publications

References 50 publications

G6PD Orchestrates Genome-Wide DNA Methylation and Gene Expression in the Vascular Wall

G6PD Orchestrates Genome-Wide DNA Methylation and Gene Expression in the Vascular Wall

Bioinformatics analysis of potential pathogenesis and risk genes of immunoinflammation-promoted renal injury in severe COVID-19

Studies in CRISPR-generated Mediterranean G6PD variant rats reveal G6PD orchestrates genome-wide DNA methylation and gene expression in vascular wall

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