Abstract P015: Factors Altering Luminal Succinate Effect Blood Pressure

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Kathleen S Hering-Smith ◽  
Weitao Huang ◽  
Fred Teran ◽  
Ryo Sato ◽  
Lee Hamm
Keyword(s):  
Target Gene ◽  
Digital Pcr ◽  
Normal Diet ◽  
Kidney Cortex ◽  
Knock Out ◽  
Acid Diet ◽  
Copy Numbers ◽  
Clearance Studies ◽  
Activity Dependent

Luminal succinate (Suc) has been reported to activate its receptor Sucnr1, stimulate renin release and increase BP in certain contexts. NaDC1 (Na + dicarboxylate cotransporter), located only on apical membrane in the proximal tubule of the kidney, reabsorbs filtered citrate and Suc, and is upregulated in acidosis. NaDC1 regulation is key in preventing stones and in maintaining acid-base homeostasis; but its role in BP regulation is not known. We postulate that luminal Suc alters BP. Our purpose was to examine the role of NaDC1, luminal Suc, and acidosis in BP regulation. To address these issues, we used NaDC1 KO (knock out) and WT (wild type) mice on normal diet or 72 hr acid diet (AD). Acidosis should lower luminal Suc due to upregulation of NaDC1 in WT mice. AD was associated with statistically significant BP decreases in both male and female WT but not in NaDC1 KO. Clearance studies compared Suc infused (SI) with non-infused NaDC1 KO and WT. ANOVA showed borderline increases between some groups: WT males on AD, BP increased from 71.48 ± 2.30 to 81.63 ± 2.16 with SI; and NaDC1 KO females on normal diet BP increased from 86.20 ± 3.98 to 96.48 ± 3.39 with SI. KO was only associated with increased BP in males on AD (p=0.05). Recently Khamaysi et al (JASN 2019) found only activity-dependent BP was altered by Suc. So, in additional studies we used telemetry (BP/T) for 24/7 monitoring of NaDC1 KO vs WT. On normal diets, mean arterial pressure (MAP) was significantly higher in KO than in WT. MAP at 9 pm: KO 122.44 ± 1.85 vs WT 110.40 ± 2.59, p <0.002, 5 am: KO 118.81 ± 2.64 vs WT 103.18 ± 4.00, p <0.01 and 8 am: KO 106.86 ± 1.28 vs 99.22 ± 2.64, p <0.02. Acidosis appeared to lessen these BP/T differences. Thus, increased luminal delivery of succinate due to KO of NaDC1 yields significant MAP increases during active periods. We examined levels of Sucnr1 in kidney cortex using droplet digital PCR (data are expressed as copy numbers of target gene in 1 ng PCR reaction). Sucnr1 expression was higher in NaDC1 KO (1343.6 ± 51) vs WT (1052.8 ± 50, p< 0.007) mice on normal diet. When fed acid diet Sucnr1 expression in KO fell (1039.6 ± 33) but increased in WT (1148 ± 50, p <0.006). In sum luminal Suc predominantly via NaDC1 reabsorption, does influence BP but this is modified by a variety of factors such as acidosis and activity.

Expression of the BDNF gene in the developing visual system of the chick

Development ◽  
1994 ◽  
Vol 120 (6) ◽  
pp. 1643-1649 ◽  
Author(s):  
K.H. Herzog ◽  
K. Bailey ◽  
Y.A. Barde
Keyword(s):  
Visual System ◽  
Ganglion Cells ◽  
Mrna Levels ◽  
Retinal Ganglion ◽  
Bdnf Gene ◽  
Bdnf Mrna ◽  
Optic Stalk ◽  
Copy Numbers ◽  
Activity Dependent

Using a sensitive and quantitative method, the mRNA levels of brain-derived neurotrophic factor (BDNF) were determined during the development of the chick visual system. Low copy numbers were detected, and BDNF was found to be expressed in the optic tectum already 2 days before the arrival of the first retinal ganglion cell axons, suggesting an early role of BDNF in tectal development. After the beginning of tectal innervation, BDNF mRNA levels markedly increased, and optic stalk transection at day 4 (which prevents subsequent tectal innervation) was found to reduce the contralateral tectal levels of BDNF mRNA. Comparable reductions were obtained after injection of tetrodotoxin into one eye, indicating that, already during the earliest stages of target encounter in the CNS, the degree of BDNF gene expression is influenced by activity-dependent mechanisms. BDNF mRNA was also detected in the retina itself and at levels comparable to those found in the tectum. Together with previous findings indicating that BDNF prevents the death of cultured chick retinal ganglion cells, these results support the idea that the tightly controlled expression of the BDNF gene might be important in the co-ordinated development of the visual system.

scholarly journals RNAi in Dictyostelium: The Role of RNA-directed RNA Polymerases and Double-stranded RNase

2002 ◽  
Vol 13 (2) ◽  
pp. 445-453 ◽  
Author(s):  
Henrik Martens ◽  
Jindrich Novotny ◽  
Jürgen Oberstrass ◽  
Theodore L. Steck ◽  
Pamela Postlethwait ◽  
...  
Keyword(s):  
Rna Polymerase ◽  
Target Gene ◽  
Helicase Domain ◽  
Limited Capacity ◽  
Hairpin Rna ◽  
Knock Out ◽  
Endogenous Gene ◽  
The One

We show that in Dictyostelium discoideum an endogenous gene as well as a transgene can be silenced by introduction of a gene construct that is transcribed into a hairpin RNA. Gene silencing was accompanied by the appearance of sequence-specific RNA ∼23mers and seemed to have a limited capacity. The threeDictyostelium homologues of the RNA-directed RNA polymerase (RrpA, RrpB, and DosA) all contain an N-terminal helicase domain homologous to the one in the dicer nuclease, suggesting exon shuffling between RNA-directed RNA polymerase and the dicer homologue. Only the knock-out of rrpA resulted in a loss of the hairpin RNA effect and simultaneously in a loss of detectable ∼23mers. However, ∼23mers were still generated by theDictyostelium dsRNase in vitro with extracts from rrpA−, rrpB−, and DosA− cells. Both RrpA and a target gene were required for production of detectable amounts of ∼23mers, suggesting that target sequences are involved in ∼23mer amplification.

PENGARUH PERSONAL BACKGROUND, POLITICAL BACKGROUND DAN PENGEATAHUAN DEWAN TENTANG ANGGARAN TERHADAP PERAN DPRD DALAM PENGAWASAN KEUANGAN DAERAH

2008 ◽  
Author(s):  
Yesi Mutia Basri ◽  
Rosliana Rosliana
Keyword(s):  
Multivariate Analysis ◽  
Significant Influence ◽  
Political Activity ◽  
Primary Data ◽  
Financial Control ◽  
Independent Variables ◽  
Dependent Variables ◽  
Political Background ◽  
Activity Dependent

This research aim to examine the influence of personal background, political background, and council budget knowledge towards the role of DPRD on region financial control. This research is motivated by the fact that individual background will effect to individual behavior on political activity. Dependent variables in this research are personal background, political background, and council budges knowledge towards the role of DPRD on region financial control Independent variables are the role of DPRD on region financial control in planning, implementing, and responsibility steps. The data in this research consist of primary data that taken from questionnaires distributed directly to respondents. The collected are from 34 Respondents that members of DPRD at Pekanbaru. Hypothesis of this research are examine by using Multivariate Analysis of Variances (MANOVA). The result of this research HI personal background political background and budget knowledge have significant influence toward the role of DPRD on region financial control in planning steps.H2 personal background, politico I background and budget knowledge have no significant influence toward the role of DPRD on region financial control in Implementing steps. H3 personal background political background and budget knowledge have no significant influence toward the role of DPRD on region financial control in Controlling steps.

scholarly journals CHOP-Dependent Stress-Inducible Expression of a Novel Form of Carbonic Anhydrase VI

1999 ◽  
Vol 19 (1) ◽  
pp. 495-504 ◽  
Author(s):  
John Sok ◽  
Xiao-Zhong Wang ◽  
Nikoleta Batchvarova ◽  
Masahiko Kuroda ◽  
Heather Harding ◽  
...  
Keyword(s):  
Carbonic Anhydrase ◽  
Target Gene ◽  
Target Genes ◽  
Direct Evidence ◽  
Nuclear Protein ◽  
Intracellular Form ◽  
Carbonic Anhydrase Vi ◽  
Responsive Element

ABSTRACT CHOP (also called GADD153) is a stress-inducible nuclear protein that dimerizes with members of the C/EBP family of transcription factors and was initially identified as an inhibitor of C/EBP binding to classic C/EBP target genes. Subsequent experiments suggested a role for CHOP-C/EBP heterodimers in positively regulating gene expression; however, direct evidence that this is the case has so far not been uncovered. Here we describe the identification of a positively regulated direct CHOP-C/EBP target gene, that encoding murine carbonic anhydrase VI (CA-VI). The stress-inducible form of the gene is expressed from an internal promoter and encodes a novel intracellular form of what is normally a secreted protein. Stress-induced expression of CA-VI is both CHOP and C/EBPβ dependent in that it does not occur in cells deficient in either gene. A CHOP-responsive element was mapped to the inducibleCA-VI promoter, and in vitro footprinting revealed binding of CHOP-C/EBP heterodimers to that site. Rescue of CA-VIexpression in c/ebpβ−/− cells by exogenous C/EBPβ and a shorter, normally inhibitory isoform of the protein known as LIP suggests that the role of the C/EBP partner is limited to targeting the CHOP-containing heterodimer to the response element and points to a preeminent role for CHOP in CA-VI induction during stress.

scholarly journals A Sex-Specific Role of Endothelial Sirtuin 3 on Blood Pressure and Diastolic Dysfunction in Female Mice

2020 ◽  
Vol 21 (24) ◽  
pp. 9744
Author(s):  
Heng Zeng ◽  
Xiaochen He ◽  
Jian-Xiong Chen
Keyword(s):  
Blood Pressure ◽  
Diastolic Dysfunction ◽  
Diastolic Function ◽  
Normal Diet ◽  
Specific Role ◽  
Sirtuin 3 ◽  
Control Female ◽  
Female Mice ◽  
Flow Reserve

Background: Heart failure with preserved ejection fraction (HFpEF) is characterized by a diastolic dysfunction and is highly prevalent in aged women. Our study showed that ablation of endothelial Sirtuin 3 (SIRT3) led to diastolic dysfunction in male mice. However, the sex-specific role of endothelial SIRT3 deficiency on blood pressure and diastolic function in female mice remains to be investigated. Methods and Results: In this study, we demonstrate that the ablation of endothelial SIRT3 in females elevated blood pressure as compared with control female mice. Diastolic function measurement also showed that the isovolumic relaxation time (IVRT) and myocardial performance index (MPI) were significantly increased, whereas the E’ velocity/A’ velocity (E’/A’) ratio was reduced in the endothelial-specific SIRT3 knockout (SIRT3 ECKO) female mice. To further investigate the regulatory role of endothelial SIRT3 on blood pressure and diastolic dysfunction in metabolic stress, SIRT3 ECKO female mice were fed a normal diet and high-fat diet (HFD) for 20 weeks. The knockout of endothelial SIRT3 resulted in an increased blood pressure in female mice fed with an HFD. Intriguingly, SIRT3 ECKO female mice + HFD exhibited impaired coronary flow reserve (CFR) and more severe diastolic dysfunction as evidenced by an elevated IVRT as compared with control female mice + HFD. In addition, female SIRT3 ECKO mice had higher blood pressure and diastolic dysfunction as compared to male SIRT3 ECKO mice. Moreover, female SIRT3 ECKO mice + HFD had an impaired CFR and diastolic dysfunction as compared to male SIRT3 ECKO mice + HFD. Conclusions: These results implicate a sex-specific role of endothelial SIRT3 in regulating blood pressure and diastolic function in mice. Deficiency of endothelial SIRT3 may be responsible for a diastolic dysfunction in aged female.

scholarly journals Loss of microglial SIRPα promotes synaptic pruning in preclinical models of neurodegeneration

2021 ◽  
Vol 12 (1) ◽  
Author(s):  
Xin Ding ◽  
Jin Wang ◽  
Miaoxin Huang ◽  
Zhangpeng Chen ◽  
Jing Liu ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Knock Out ◽  
Classical Complement Pathway ◽  
Synaptic Remodeling ◽  
The Central Nervous System ◽  
System Activation ◽  
Knock Out Mice ◽  
Synaptic Pruning

AbstractMicroglia play a key role in regulating synaptic remodeling in the central nervous system. Activation of classical complement pathway promotes microglia-mediated synaptic pruning during development and disease. CD47 protects synapses from excessive pruning during development, implicating microglial SIRPα, a CD47 receptor, in synaptic remodeling. However, the role of microglial SIRPα in synaptic pruning in disease remains unclear. Here, using conditional knock-out mice, we show that microglia-specific deletion of SIRPα results in decreased synaptic density. In human tissue, we observe that microglial SIRPα expression declines alongside the progression of Alzheimer’s disease. To investigate the role of SIRPα in neurodegeneration, we modulate the expression of microglial SIRPα in mouse models of Alzheimer’s disease. Loss of microglial SIRPα results in increased synaptic loss mediated by microglia engulfment and enhanced cognitive impairment. Together, these results suggest that microglial SIRPα regulates synaptic pruning in neurodegeneration.

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