scholarly journals Genome-wide analysis of gestational gene-environment interactions in the developing kidney

2014 ◽  
Vol 46 (17) ◽  
pp. 655-670 ◽  
Author(s):  
Lei Yan ◽  
Xiao Yao ◽  
Dimcho Bachvarov ◽  
Zubaida Saifudeen ◽  
Samir S. El-Dahr
Keyword(s):  
Gene Expression ◽  
Salt Intake ◽  
Transcriptional Profiling ◽  
In Silico Analysis ◽  
Gene Environment ◽  
Genome Wide ◽  
High Salt Intake ◽  
Excess Salt Intake ◽  
Developing Kidney ◽  
Cell Matrix Interactions

The G protein-coupled bradykinin B2 receptor (Bdkrb2) plays an important role in regulation of blood pressure under conditions of excess salt intake. Our previous work has shown that Bdkrb2 also plays a developmental role since Bdkrb2−/− embryos, but not their wild-type or heterozygous littermates, are prone to renal dysgenesis in response to gestational high salt intake. Although impaired terminal differentiation and apoptosis are consistent findings in the Bdkrb2−/− mutant kidneys, the developmental pathways downstream of gene-environment interactions leading to the renal phenotype remain unknown. Here, we performed genome-wide transcriptional profiling on embryonic kidneys from salt-stressed Bdkrb2 +/+ and Bdkrb2 −/− embryos. The results reveal significant alterations in key pathways regulating Wnt signaling, apoptosis, embryonic development, and cell-matrix interactions. In silico analysis reveal that nearly 12% of differentially regulated genes harbor one or more Pax2 DNA-binding sites in their promoter region. Further analysis shows that metanephric kidneys of salt-stressed Bdkrb2−/− have a significant downregulation of Pax2 gene expression. This was corroborated in Bdkrb2 −/−; Pax2 GFP+/tg mice, demonstrating that Pax2 transcriptional activity is significantly repressed by gestational salt-Bdkrb2 interactions. We conclude that gestational gene ( Bdkrb2) and environment (salt) interactions cooperate to impact gene expression programs in the developing kidney. Suppression of Pax2 likely contributes to the defects in epithelial survival, growth, and differentiation in salt-stressed BdkrB2 −/− mice.

scholarly journals Susceptibility to metanephric apoptosis in bradykinin B2 receptor null mice via the p53-Bax pathway

2006 ◽  
Vol 291 (3) ◽  
pp. F670-F682 ◽  
Author(s):  
Hao Fan ◽  
Jana Stefkova ◽  
Samir S. El-Dahr
Keyword(s):  
Gene Expression ◽  
Salt Intake ◽  
Ectopic Expression ◽  
Renal Dysplasia ◽  
Genetic Mutation ◽  
Metanephric Mesenchyme ◽  
High Salt Intake ◽  
Apoptosis Index ◽  
Apoptotic Activity ◽  
Bax Gene

In response to gestational high salt intake, BdkrB2−/− embryos acquire an aberrant renal phenotype mimicking renal dysplasia in humans. Genetic analysis identified p53 as a mediator of the renal dysplasia in salt-stressed BdkrB2−/− mice, acting partly via repression of terminal epithelial differentiation genes. The present study tested the hypothesis that inactivation of BdkrB2 predisposes the salt-stressed embryo to p53-mediated metanephric apoptosis. Newborn BdkrB2−/− pups exhibited hyperphosphorylation of metanephric p53 on serine 20 (mouse serine 23), a modification known to increase p53 stability and apoptotic activity. As a result, there was widespread, ectopic expression of p53 in the BdkrB2−/− kidney. However, no differences were found in the apoptosis index or gene expression in BdkrB2−/− and +/+ kidneys, indicating that p53 stabilization as a result of BdkrB2 inactivation is not sufficient to induce metanephric apoptosis. On gestational salt stress, fulminant metanephric apoptosis and enhanced Bax gene expression occurred in BdkrB2−/− but not their +/− or +/+ littermates. Germline deletion of p53 from BdkrB2−/− mice prevented Bax activation and normalized the apoptosis index. Rescue of metanephric apoptosis in BdkrB2−/− mice was similarly achieved by Bax gene deletion. Aberrant apoptosis in salt-stressed BdkrB2−/− mice was triggered on embryonic day E15.5 and involved both ureteric bud (UB) and metanephric mesenchyme-derived nephron elements. Cultured E12.5 salt-stressed BdkrB2−/− metanephroi manifested stunted UB branching compared with +/− and +/+ littermates; the abnormal UB branching was corrected by p53 deletion. Our results suggest a model whereby a seemingly silent genetic mutation of BdkrB2 predisposes mice to renal dysplasia by creating a “preapoptotic” state through p53 activation.

Abstract P639: Attenuation of Renal Inner Medullary Circadian Clock Gene Expression in Response to High Salt Intake is Dependent on the Endothelin B Receptor

Hypertension ◽  
2015 ◽  
Vol 66 (suppl_1) ◽  
Author(s):  
Joshua S Speed ◽  
Kelly A Hyndman ◽  
Malgorzata Kasztan ◽  
Jermaine G Johnston ◽  
Martin E Young ◽  
...  
Keyword(s):  
Gene Expression ◽  
Circadian Clock ◽  
Clock Gene ◽  
Salt Intake ◽  
Time Of Day ◽  
High Salt ◽  
Circadian Clock Gene ◽  
Clock Gene Expression ◽  
High Salt Intake ◽  
Renal Inner Medulla

Our lab has recently shown that ETB deficient (ETB def) rats have a time of day dependent impairment in their ability to excrete a Na+ load. These observations suggest an interaction between renal ETB receptors and circadian mechanisms that regulate renal tubular Na+ transport and excretion. Given that knockout of the circadian clock gene Bmal1 reduces blood pressure in mice, we hypothesized that a high salt intake impairs the clock mechanism in the renal inner medulla in an ETB dependent manner. Transgenic control (Tg con) or ETB def rats were fed normal (NS, 0.8% NaCl) or high (HS, 4% NaCl) salt for two weeks. In one group, rats were euthanized every 4 hours beginning at zeitgeber time 0 (lights on) for tissue collection (and subsequent assessment of circadian clock genes), while in a second group of rats urine was collected in 12-hour intervals (active vs. inactive). Consistent with our hypothesis, we observed that HS abolished the normal oscillation in Bmal1 expression in the renal inner medulla of Tg con rats, and effect not observed in ETB def rats. Interestingly, renal production of ET-1, was significantly higher during the active period vs. inactive period in both NS (3.6±1.1 vs. 0.8±0.2 pg/12hr respectively) and HS (9.2±4.1 vs. 1.6±0.3 pg/12hr respectively) fed Tg con rats. There was no time-of-day-dependent difference in ET-1 excretion in ETB def rats on NS (6.6±2.2 vs. 4.6±1.7 pg/12hr respectively), although this pattern was restored in ETB def rats fed HS (2.2±1.0 vs. 9.2±2.5 pg/12hr inactive vs. active). Taken together, these data indicate that an increase in renal ET-1/ETB activation in response to HS modulates inner medullary clock gene expression to promote renal Na+ excretion.

scholarly journals A genome-wide transcriptional analysis of morphology determination inCandida albicans

2013 ◽  
Vol 24 (3) ◽  
pp. 246-260 ◽  
Author(s):  
Patricia L. Carlisle ◽  
David Kadosh
Keyword(s):  
Gene Expression ◽  
Fungal Infections ◽  
Transcriptional Profiling ◽  
Expression Patterns ◽  
Global Gene Expression ◽  
Transcriptional Analysis ◽  
Specific Gene ◽  
Genome Wide ◽  
A Genome ◽  
Genetically Manipulated

Candida albicans, the most common cause of human fungal infections, undergoes a reversible morphological transition from yeast to pseudohyphal and hyphal filaments, which is required for virulence. For many years, the relationship among global gene expression patterns associated with determination of specific C. albicans morphologies has remained obscure. Using a strain that can be genetically manipulated to sequentially transition from yeast to pseudohyphae to hyphae in the absence of complex environmental cues and upstream signaling pathways, we demonstrate by whole-genome transcriptional profiling that genes associated with pseudohyphae represent a subset of those associated with hyphae and are generally expressed at lower levels. Our results also strongly suggest that in addition to dosage, extended duration of filament-specific gene expression is sufficient to drive the C. albicans yeast-pseudohyphal-hyphal transition. Finally, we describe the first transcriptional profile of the C. albicans reverse hyphal-pseudohyphal-yeast transition and demonstrate that this transition involves not only down-regulation of known hyphal-specific, genes but also differential expression of additional genes that have not previously been associated with the forward transition, including many involved in protein synthesis. These findings provide new insight into genome-wide expression patterns important for determining fungal morphology and suggest that in addition to similarities, there are also fundamental differences in global gene expression as pathogenic filamentous fungi undergo forward and reverse morphological transitions.

scholarly journals Genome-wide transcriptional profiling uncovers a similar oligodendrocyte-related transcriptional response to acute and chronic alcohol drinking in the amygdala

2021 ◽  
Author(s):  
Sharvari Narendra ◽  
Claudia Klengel ◽  
Bilal Hamzeh ◽  
Drasti Patel ◽  
Joy Otten ◽  
...  
Keyword(s):  
Gene Expression ◽  
Alcohol Drinking ◽  
Brain Area ◽  
Transcriptional Profiling ◽  
Expression Patterns ◽  
Transcriptional Response ◽  
Histone Deacetylation ◽  
Regulatory Pathways ◽  
Genome Wide ◽  
A Genome

AbstractAlcohol intake progressively increases after prolonged consumption of alcohol, but relatively few new therapeutics targeting development of alcohol use disorder (AUD) have been validated. Here, we conducted a genome-wide RNA-sequencing (RNA-seq) analysis in mice exposed to different modes (acute vs chronic) of ethanol drinking. We focused on transcriptional profiles in the amygdala including the central and basolateral subnuclei, a brain area previously implicated in alcohol drinking and seeking, demonstrating distinct gene expression patterns and canonical pathways induced by both acute and chronic intake. Surprisingly, both drinking modes triggered similar transcriptional changes, including up-regulation of ribosome-related/translational pathways and myelination pathways, and down-regulation of chromatin binding and histone modification. Notably, multiple genes that were significantly regulated in mouse amygdala with alcohol drinking, including Atp2b1, Slc4a7, Nfkb1, Nts, and Hdac2, among others had previously been associated with human AUD via GWAS or other genomic studies. In addition, analyses of hub genes and upstream regulatory pathways predicted that voluntary ethanol consumption affects epigenetic changes via histone deacetylation pathways, oligodendrocyte and myelin function, and oligodendrocyte-related transcriptional factor, Sox17.Overall, our results suggest that the transcriptional landscape in the central and basolateral subnuclei of the amygdala is sensitive to voluntary alcohol drinking. They provide a unique resource of gene expression data for future translational studies examining transcriptional mechanisms underlying the development of AUD due to alcohol consumption.

scholarly journals 3’ RNA sequencing for robust and low-cost gene expression profiling

2021 ◽  
Author(s):  
Eric Charpentier ◽  
Marine Cornec ◽  
Solenne Dumont ◽  
Dimitri Meistermann ◽  
Philippe Bordron ◽  
...  
Keyword(s):  
Gene Expression ◽  
Rna Sequencing ◽  
Low Cost ◽  
Transcriptional Profiling ◽  
Digital Gene Expression ◽  
End User ◽  
Flow Cells ◽  
Rna Profiling ◽  
Genome Wide ◽  
Standard Procedures

Abstract 3’seq-RNA Profiling (3’SRP) approach is based on multiplexing samples and molecular indexing mRNA in order to drive genome-wide transcriptional profiling at reasonable cost in comparison to standard RNA-sequencing. The protocol is performed according to the 3′-digital gene expression (3′-DGE) approach developed by the Broad institute. The libraries are prepared from small amounts of total RNA where the mRNA poly(A) tails are tagged with universal adapters, well-specific barcodes and unique molecular identifiers (UMIs). We have improved the fragmentation step by implementing tagmentation based on the activity of a bead-linked transposome. This technique allows sample multiplexing on 96-well plates. Libraries are then sequenced using standard procedures, e.g. on Hiseq2500 or NovaSeq 6000 SP Flow Cells. We have developed a snakemake pipeline including every analysis step from raw fastq de-multiplexing to functional annotation of the differentially expressed genes, producing a complete HTML report for end-user.

scholarly journals Thromboxane A2 Receptor Antagonist (ONO-8809) Attenuates the Renal Disorders Caused by Salt-Overload in Stroke-Prone Spontaneously Hypertensive Rats

2021 ◽  
Author(s):  
Yusuke Nagatani ◽  
Toshihide Higashino ◽  
Kosho Kinoshita ◽  
Hideaki Higashino
Keyword(s):  
Gene Expression ◽  
Spontaneously Hypertensive Rats ◽  
Salt Intake ◽  
Thromboxane A2 ◽  
High Salt ◽  
Hypertensive Rats ◽  
Salt Loading ◽  
Spontaneously Hypertensive ◽  
Oxidative Stresses ◽  
High Salt Intake

Background. Epidemiological and clinical studies demonstrated that excessive salt intake causes severe hypertension and exacerbated organ derangement such as chronic kidney disease (CKD). In this study, we focused on evaluating histological and gene-expression findings in the kidney using stroke-prone spontaneously hypertensive rats (SHRSP) with high-salt intake and thromboxane A2/ prostaglandin H2 receptor (TPR) blocker ONO-8809. Methods. SHRSP aged 6 weeks were divided into three groups eating normal chow containing 0.4% NaCl, 2.0%NaCl, or 2.0%NaCl +ONO-8809 (0.6mg/kg p.o. daily). Histological analyses with immunohistochemistry and a gene-expression assay with a DNA kidney microarray were performed after 8 weeks. Results. The following changes were observed with high-salt intake. Glomerular sclerotic changes were remarkably observed in the juxtaglomerular cortex areas. ED1, MCP-1, nitrotyrosine, and HIF-1α staining areas were increased in the glomeruli and interstitial portion. Tbxa2r which encodes TPR, Prcp, and Car7 were significantly underexpressed in the kidney. The plasma 8-isoprostane level was significantly elevated, and was attenuated with ONO-8809 treatment. Conclusion. TXA2 and oxidative stresses exaggerated renal dysfunction in salt-loading SHRSP, and ONO-8809 as a TPR blocker suppressed these changes. Therefore, ONO-8809 is a candidate drug to prevent CKD for hypertensive patients associated with high-salt intake.

Impact of salt on cardiac differential gene expression and coronary lesion in normotensive mineralocorticoid-treated mice

2012 ◽  
Vol 302 (9) ◽  
pp. R1025-R1033 ◽  
Author(s):  
Qing Wang ◽  
Andrea A. Domenighetti ◽  
Stephan C. Schäfer ◽  
Johanns Weber ◽  
Alexandra Simon ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cardiac Hypertrophy ◽  
Protein Expression ◽  
Vascular Remodeling ◽  
Salt Intake ◽  
High Salt ◽  
Cardiovascular Remodeling ◽  
High Salt Intake ◽  
Gene And Protein Expression ◽  
Differential Gene

We previously reported that excess of deoxycorticosterone-acetate (DOCA)/salt-induced cardiac hypertrophy in the absence of hypertension in one-renin gene mice. This model allows us to study molecular mechanisms of high-salt intake in the development of cardiovascular remodeling, independently of blood pressure in a high mineralocorticoid state. In this study, we compared the effect of 5-wk low- and high-salt intake on cardiovascular remodeling and cardiac differential gene expression in mice receiving the same amount of DOCA. Differential gene and protein expression was measured by high-density cDNA microarray assays, real-time PCR and Western blot analysis in DOCA-high salt (HS) vs. DOCA-low salt (LS) mice. DOCA-HS mice developed cardiac hypertrophy, coronary perivascular fibrosis, and left ventricular dysfunction. Differential gene and protein expression demonstrated that high-salt intake upregulated a subset of genes encoding for proteins involved in inflammation and extracellular matrix remodeling (e.g., Col3a1, Col1a2, Hmox1, and Lcn2). A major subset of downregulated genes encoded for transcription factors, including myeloid differentiation primary response (MyD) genes. Our data provide some evidence that vascular remodeling, fibrosis, and inflammation are important consequences of a high-salt intake in DOCA mice. Our study suggests that among the different pathogenic factors of cardiac and vascular remodeling, such as hypertension and mineralocorticoid excess and sodium intake, the latter is critical for the development of the profibrotic and proinflammatory phenotype observed in the heart of normotensive DOCA-treated mice.

scholarly journals The sodium-activated sodium channel is expressed in the rat kidney thick ascending limb and collecting duct cells and is upregulated during high salt intake

2012 ◽  
Vol 303 (1) ◽  
pp. F105-F109 ◽  
Author(s):  
Lucienne S. Lara ◽  
Ryousuke Satou ◽  
Camille R. T. Bourgeois ◽  
Alexis A. Gonzalez ◽  
Andrea Zsombok ◽  
...  
Keyword(s):  
Gene Expression ◽  
Epithelial Cells ◽  
Salt Intake ◽  
Collecting Duct ◽  
Rat Kidney ◽  
Extracellular Fluid ◽  
High Salt ◽  
Thick Ascending Limb ◽  
Principal Cells ◽  
High Salt Intake

Increased dietary salt triggers oxidative stress and kidney injury in salt-sensitive hypertension; however, the mechanism for sensing increased extracellular Na+ concentration ([Na+]) remains unclear. A Na+-activated Na+ channel (Na sensor) described in the brain operates as a sensor of extracellular fluid [Na+]; nonetheless, its presence in the kidney has not been established. In the present study, we demonstrated the gene expression of the Na sensor by RT-PCR and Western blotting in the Sprague-Dawley rat kidney. Using immunofluorescence, the Na sensor was localized to the luminal side in tubular epithelial cells of collecting ducts colocalizing with aquaporin-2, a marker of principal cells, and in thick ascending limb, colocalizing with the glycoprotein Tamm-Horsfall. To determine the effect of a high-salt diet (HSD) on Na sensor gene expression, we quantified its transcript and protein levels primarily in renal medullas from control rats and rats subjected to 8% NaCl for 7 days ( n = 5). HSD increased Na sensor expression levels (mRNA: from 1.2 ± 0.2 to 5.1 ± 1.3 au; protein: from 0.98 ± 0.15 to 1.74 ± 0.28 au P < 0.05) in the kidney medulla, but not in the cortex. These data indicate that rat kidney epithelial cells of the thick ascending limb and principal cells of the collecting duct possess a Na sensor that is upregulated by HSD, suggesting an important role in monitoring changes in tubular fluid [Na+].

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