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.

scholarly journals Genetic mutation of recombination activating gene 1 in Dahl salt-sensitive rats attenuates hypertension and renal damage

2013 ◽  
Vol 304 (6) ◽  
pp. R407-R414 ◽  
Author(s):  
David L. Mattson ◽  
Hayley Lund ◽  
Chuanling Guo ◽  
Nathan Rudemiller ◽  
Aron M. Geurts ◽  
...  
Keyword(s):  
Immune Cells ◽  
Renal Damage ◽  
Salt Intake ◽  
Disease Process ◽  
Genetic Mutation ◽  
High Salt ◽  
Tubular Damage ◽  
Arterial Blood ◽  
High Salt Intake ◽  
Recombination Activating Gene

Hypertension and renal damage in Dahl SS rats are associated with increased infiltrating immune cells in the kidney. To examine the role of infiltrating immune cells in this disease process, a zinc finger nuclease targeting bases 672–706 of recombination-activating gene 1 (Rag1) was injected into the pronucleus of Dahl SS (SS/JrHsdMcwi) strain embryos and implanted in pseudopregnant females. This strategy yielded a rat strain with a 13-base frame-shift mutation in the target region of Rag1 and a deletion of immunoreactive Rag1 protein in the thymus. Flow cytometry demonstrated that the Rag1-null mutant rats have a significant reduction in T and B lymphocytes in the circulation and spleen. Studies were performed on SS and Rag1-null rats fed a 4.0% NaCl diet for 3 wk. The infiltration of T cells into the kidney following high-salt intake was significantly blunted in the Rag1-null rats (1.7 ± 0.6 × 105 cells/kidney) compared with the Dahl SS (5.6 ± 0.9 × 105 cells/kidney). Accompanying the reduction in infiltration of immune cells in the kidney, mean arterial blood pressure and urinary albumin excretion rate were significantly lower in Rag1-null mutants (158 ± 3 mmHg and 60 ± 16 mg/day, respectively) than in SS rats (180 ± 11 mmHg and 251 ± 37 mg/day). Finally, a histological analysis revealed that the glomerular and tubular damage in the kidneys of the SS rats fed a high-salt diet was also attenuated in the Rag1 mutants. These studies demonstrate the importance of renal infiltration of immune cells in the pathogenesis of hypertension and renal damage in Dahl SS rats.

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 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+].

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.

Prevalence, Biochemical and Clinical Characteristics of Resistant Hypertension

2018 ◽  
Vol 69 (10) ◽  
pp. 2845-2849
Author(s):  
Daniela Gurgus ◽  
Elena Ardeleanu ◽  
Carmen Gadau ◽  
Roxana Folescu ◽  
Ioan Tilea ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Cardiovascular Disease ◽  
Resistant Hypertension ◽  
Clinical Characteristics ◽  
Salt Intake ◽  
Target Organ Damage ◽  
Multivariate Logistic Regression Analysis ◽  
Organ Damage ◽  
Left Ventricular ◽  
High Salt Intake

The objectives of the present study were to evaluate the prevalence of resistant hypertension (RH) in primary care setting and to analyse its biochemical and clinical characteristics. After 3 months of treatment and evaluation, 721 (14.01%) of 5,146 patients with hypertension did not reach target office blood pressure of [ 140/90 mmHg. After exclusion of �white-coat effect� with ambulatory blood pressure, of secondary and pseudo- resistant hypertension, prevalence of RH was 6.74%. Lifestyle factors associated with RH were physical inactivity, obesity, high salt intake, smoking and excessive alcohol ingestion. Compared to controlled hypertension, RH patients presented higher incidence of family history of cardiovascular disease (38.90% vs 25.94%), diabetes mellitus (34.87% vs 19.01%), impaired fasting glucose (21.91% vs 19.07%), target organ damage (29.1% vs 15.95%), and cardiovascular disease (27.09% vs 17.06%). Dyslipidaemia (52.90% vs 42.03%), fasting plasma glucose (116.10�38.9 vs 107.80�37.2), HbA1c (6.41�1.42 vs 5.96�0.94), serum creatinine (1.09�0.27 vs 1.03�0.24) and microalbuminuria (21.90% vs 10.95%) were significantly higher in RH. Predictors of RH, determined by a multivariate logistic regression analysis were left ventricular hypertrophy (OD 2.14, 95% CI 1.32-3.69), renal impairment expressed as eGFR [ 60 ml/min/1.73m2 (OD 1.62, 95% CI 1.21-2.21) and the presence of cardiovascular disease (OD 1.48, 95% CI 1.02-2.16).

scholarly journals Salt Intake in Nigeria: a nationwide population survey

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
A.N Odili ◽  
B.S Chori ◽  
B Danladi ◽  
P.C Nwakile ◽  
J.O Ogedengbe ◽  
...  
Keyword(s):  
Salt Intake ◽  
Sodium Intake ◽  
Population Analysis ◽  
Cost Effective ◽  
Rural Site ◽  
Urban Site ◽  
Funding Source ◽  
Salt Reduction ◽  
High Salt Intake ◽  
The Impact

Abstract Background Population wide salt reduction programmes are cost effective strategies for control of cardiovascular diseases (CVDs). Obtaining a nationwide salt consumption data in a multi-cultural setting as Nigeria's is key for proper implementation and monitoring of such strategy. Methods We measured sodium in 24-hour urine of free-living adult Nigerians selected from an urban and a rural site each from the 6 geopolitical zones of Nigeria to evaluate patterns of salt intake and its associations with blood pressures (BP). Results Across the 12 sites, sodium intake ranged from 97.9 in the rural South-South to 210 mmol/day in the urban site of the same zone. Overall, the median (IQR) daily sodium intake was 143.5 (97.8) mmol; with higher (p=0.0028) levels among the urban 149.7 (113.8) compared to the rural 133.1 (105.2) dwellers. Overall, 20% of the subjects consumed less than the recommended 2g (86mmol) of sodium daily. After adjustment for age, sex and BMI; sodium intake and BP (systolic and diastolic) were positively associated in 8 out of the 12 sites; significantly so in 2 (p&lt;0.05) for systolic. Within population analysis; which included 973 individuals, increasing sodium intake tended (not significantly) to increase SBP but decrease DBP. However, among subjects whose sodium intake was in excess of 257mmol/day, a 100 mmol/day increase in sodium intake was significantly (p=0.04) associated with a 3.3 mmHg increase in SBP. Conclusion Salt intake among Nigerians is higher than the recommended. The impact of sodium intake on BP appears to be evident only among individuals with high salt intake. Funding Acknowledgement Type of funding source: Foundation. Main funding source(s): Wellcome Trust

scholarly journals High Salt Intake and Stroke: Meta-analysis of the Epidemiologic Evidence

2012 ◽  
Vol 18 (8) ◽  
pp. 691-701 ◽  
Author(s):  
Xiu-Yang Li ◽  
Xian-Lei Cai ◽  
Ping-Da Bian ◽  
Liu-Ru Hu
Keyword(s):  
Salt Intake ◽  
Meta Analysis ◽  
High Salt ◽  
Epidemiologic Evidence ◽  
High Salt Intake
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