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DNA de novo (de)Methylation in the Kidney Contributes to Salt-Induced Hypertension [RNA-seq]

ABSTRACT: Numerous adult diseases involving tissues that consist primarily of non-dividing cells are associated with changes in DNA methylation. It suggests a role for de novo methylation or demethylation of DNA, which is catalyzed by DNA methyltransferase 3 (Dnmt3) and ten-eleven translocases (Tet). However, the contribution of DNA de novo (de)methylation to these diseases remains nearly completely unproven. Broad changes in DNA methylation occurred within days in the renal outer medulla of Dahl SS rats fed a high-salt diet, a classic model of hypertension. Intra-renal administration of anti-Dnmt3a/Tet3 GapmeR’s attenuated high salt-induced hypertension in SS rats. The high salt diet induced differential expression of 1,712 genes in the renal outer medulla. Remarkably, the differential expression of 76% of these genes were prevented by anti-Dnmt3a/Tet3 GapmeR’s. The genes differentially expressed in response to the GapmeR’s were involved in the regulation of metabolism and inflammation and were significantly enriched for genes showing differential methylation in response to the GapmeR’s. These data indicate DNA de novo (de)methylation in the kidney contributes to the development of hypertension in SS rats. The findings should help to shift the paradigm of DNA methylation research in diseases involving non-dividing cells from correlative analysis to functional and mechanistic studies.

ORGANISM(S): Rattus norvegicus

PROVIDER: GSE114334 | GEO | 2019/02/13

REPOSITORIES: GEO

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DNA de novo (de)Methylation in the Kidney Contributes to Salt-Induced Hypertension [RRBS-seq]

Project description:Numerous adult diseases involving tissues that consist primarily of non-dividing cells are associated with changes in DNA methylation. It suggests a role for de novo methylation or demethylation of DNA, which is catalyzed by DNA methyltransferase 3 (Dnmt3) and ten-eleven translocases (Tet). However, the contribution of DNA de novo (de)methylation to these diseases remains nearly completely unproven. Broad changes in DNA methylation occurred within days in the renal outer medulla of Dahl SS rats fed a high-salt diet, a classic model of hypertension. Intra-renal administration of anti-Dnmt3a/Tet3 GapmeR’s attenuated high salt-induced hypertension in SS rats. The high salt diet induced differential expression of 1,712 genes in the renal outer medulla. Remarkably, the differential expression of 76% of these genes were prevented by anti-Dnmt3a/Tet3 GapmeR’s. The genes differentially expressed in response to the GapmeR’s were involved in the regulation of metabolism and inflammation and were significantly enriched for genes showing differential methylation in response to the GapmeR’s. These data indicate DNA de novo (de)methylation in the kidney contributes to the development of hypertension in SS rats. The findings should help to shift the paradigm of DNA methylation research in diseases involving non-dividing cells from correlative analysis to functional and mechanistic studies.

2019-02-13 | GSE114333 | GEO

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Dietary Effects on T Cell Methylomes and Functional Inhibition of DNA Methyltransferase Attenuates Salt-Sensitive Hypertension and Renal Damage in Dahl SS Rat

Project description:The Dahl salt-sensitive (SS) rat is an established model of hypertension and renal damage that is accompanied with an activation of the immune system in the response to a high salt diet. Investigations into the effects of sodium-independent and –dependent components of the diet were shown to affect the disease phenotype with Dahl SS/JrHsdMcwi (SS/MCW) rats maintained on a purified diet (AIN-76A) presenting with a more severe phenotype relative to the grain-fed Dahl SS/JrHsdMcwiCrl rat (SS/CRL). Recently, T cells isolated from the kidneys of the two strains unveiled that transcriptomic and functional differences may contribute to the susceptibility of hypertension and renal damage. Since contributions of the immune system, environment and diet are documented to alter this phenotype, this present study examined the epigenetic profile of T cells isolated from the periphery and the kidney from these strains. In response to high salt challenge, the methylome of T cells isolated from the kidney of SS/MCW exhibit significantly more differentially methylated regions with a preference for hypermethylation compared to the SS/CRL kidney T cells. Circulating T cells exhibited similar methylation profiles between the strains. Utilizing transcriptomic data from T cells isolated from the same animals upon which the DNA methylation analysis was performed, a predominant negative correlation was observed between gene expression and DNA methylation in all groups. Lastly, inhibition of DNA methyltransferases blunted salt-induced hypertension and renal damage in the SS/MCW rats providing a functional role for methylation. The study demonstrated the influence of epigenetic modifications to immune cell function, highlighting the need for further investigations.

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Purine and TCA measurements in salt sensitive (SS) hypertension

Project description:SS rats were surgically implanted with a chronic servo-control cuff, the purpose of which is to maintain normal pressure to the left kidney while the right kidney is exposed to high blood pressure. After 7 days of high salt treatment, which induces high blood pressure in the SS rat, rats were anesthetized with pentobarbital, kidneys were flushed and removed. The renal medulla was separated from the cortex using scissors, and the renal medullas were frozen in liquid nitrogen and stored at -80 C.

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Project description:Serum and glucocorticoid-induced kinase 1 (SGK1) activates the epithelial sodium channel (eNaC) in tubules. We examined renal SGK1 abundance in salt-adaptation and in salt-sensitive hypertension. Sprague-Dawley and Dahl salt-sensitive rats were placed on either 8% or 0.3% NaCl diets for 10 days. Plasma aldosterone levels were approximately 2.5-fold greater on 0.3% versus 8% NaCl diets in both rat strains. Both serum and glucocorticoid-induced kinase 1 transcript and protein abundance were less (P<0.01) in Sprague-Dawley rats and greater (P<0.01) in Dahl salt-sensitive rats on 8% versus 0.3% NaCl diets. The cDNA sequences of serum and glucocorticoid-induced kinase 1 in both strains of rat were the same. The present results provide evidence that the abundance of serum and glucocorticoid-induced kinase 1 in rat kidney may play a role in salt adaptation and the pathogenesis of hypertension and suggests that aldosterone is not the primary inducer of SGK1 in the Sprague-Dawley rat. Keywords = Rattus norvegicus, Sprague Dawley, Dahl SS/Jr, kidney, NaCl diet Keywords: other

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Project description:Arhgef11 is a Rho guanine nucleotide exchange factor previously implicated in kidney injury in the Dahl salt-sensitive rat (SS-WT). Through exchange of GDP for GTP, Arhgef11 regulates cytoskeletal structure, function, and cell-cell contacts through a variety of stimuli (e.g., G-protein coupled receptors, growth factors, and shear stress). We studied the SS-Arhgef11-/- rat model at 4-12 weeks of age under low and high salt (0.3% or 2% NaCl). To better understand the molecular mechanisms associated with renal protection from loss of Arhgef11, MS/MS proteomics was performed on kidney from SS-Arhgef11-/- and SS-WT at week 12 (low-salt). At week 12, 1017 genes and 363 proteins were observed. In summary, in vivo phenotyping provides strong evidence that increased Arhgef11 expression in the Dahl S rat leads to actin cytoskeleton mediated changes in cell morphology and cell function (impaired reuptake filtered protein) that promote kidney injury, hypertension, and decline in kidney function.

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