bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P135: Bone Mineral Density is Associated With Vascular Endothelial Function and Arterial Stiffness in Apparently Normal Population From China
Authors: Liu Huan , Hong Yongqiang , Wu Xiuqin , Wang Hongyu , Liu Jinbo , Zhao Hongwei
Published: December 2018

Objective:
To evaluate the relation of vascular parameters with bone mineral density (BMD) in the apparently normal population.

Background:
Vascular parameters including brachial arterial flow-mediated vasodilatation (FMD), brachial ankle pulse wave velocity (ba-PWV) and ankle brachial index (ABI), are reported associated with bone health. However, prior investigations have been limited to highly selected samples.

Methods:
We studied 165 individuals without a history of cardiovascular disease in the Chinese Arteriosclerosis Series Evaluation-She Minority Study (CASE-SMS) cohort (mean age 46.94±11.23 years, 59.4% women). BMD was quantified by dual-energy X-ray absorptiometry (DXA).

Results:
Age-adjusted analysis showed there was no difference in FMD, ba-PWV, ABI, lumbar vertebra BMD and left hip BMD between male, premenopausal female and postmenopausal female (all p>0.05). Multivariable linear analysis showed that FMD (B=0.005, p=0.016) and ba-PWV (B=-0.009, p=0.014) were both associated with lumbar vertebra BMD independently of each other. Multivariable logistic analysis showed FMD and ba-PWV were both related to low BMD in total (FMD OR 0.860, 95% CI 0.802 to 0.922, p<0.001; ba-PWV OR 1.494, 95% CI 1.275 to 1.751, p<0.001), male (FMD OR 0.861, 95% CI 0.757 to 0.979, p=0.022; ba-PWV OR 1.523, 95% CI 1.190 to 1.951, p=0.001), premenopausal female (FMD OR 0.842, 95% CI 0.734 to 0.966, p=0.014; ba-PWV OR 1.421, 95% CI 1.063 to 1.899, p=0.018) and postmenopausal female population (FMD OR 0.825, 95% CI 0.715 to 0.952, p=0.008; ba-PWV OR 1.740, 95% CI 1.187 to 2.551, p=0.004). In all the analyses, ABI was not associated with BMD (all p>0.05).

Conclusion:
There was no difference in FMD, ba-PWV, ABI, lumbar vertebra BMD and left hip BMD between male, premenopausal female and postmenopausal female after adjusting for age. FMD and ba-PWV were independently associated with lumbar vertebra BMD and low BMD. However, ABI was not associated with BMD.
Abstract P153: Crosstalk Between Vascular Redox and Calcium Signalling in Hypertension Involves Transient Receptor Potential Melastatin 2 (TRPM2) Channel
Authors: Alves-Lopes Rhéure , Neves Karla B , Anagnostopoulou Aikaterini , Lacchini Silvia , Montezano Augusto C , Touyz Rhian M
Published: December 2018

Mechanisms involved in redox-sensitive calcium signalling in hypertension are elusive. TRPM2 is a cation channel permeable to Ca2+ that is highly sensitive to increased levels of H2O2. TRPM2 also regulates Na+ influx, which may influence the sodium-calcium exchanger (NCX), which in reverse mode, promotes Ca2+ influx. We hypothesise that vascular oxidative stress in hypertension causes TRPM2 activation, increased influx of Ca2+ and vascular dysfunction. Vascular smooth muscle cells (VSMCs) from hypertensive and normotensive subjects and mesenteric arteries from wildtype (WT) and hypertensive LinA3 mice (human renin-expressing mice) were used. H2O2 levels were increased in hypertensive VSMCs (% of control:188.6±36.3), followed by increased activity of TRPM2 modulator PARP1 (% of control: 158.4±18.7), effect reversed by PEG-Catalase (104.1±7.0), suggesting an event regulated by H2O2. Higher calcium influx in hypertensive VSMCs (AUC NT 15710±812.3 vs HT 21440 ± 1685) was normalized by PEG-Catalase, and TRPM2 inhibitors (2-APB, Olaparib and 8-Br-cADPR) and by Na+ depletion and NCX inhibitors (Benzamil, KB-R7943 and YM 244769). Phosphorylation of the pro-contractile signaling protein, MLC20 in VSMCs from hypertensive patients (% of control 186.3±21.5) and agonist-induced vascular responses in LinA3 mice (max response: NT 0.29±6.7 vs HT 9.3±0.5) were attenuated by inhibitors of TRPM2 and NCX. These results demonstrate that in hypertension vascular oxidative stress influences TRPM2-mediated Ca2+ and Na+ homeostasis, through processes that involve NCX activation. Our findings identify novel signalling pathways linking ROS-TRPM2-Ca2+-Na+, which may play a role in hypercontractile responses in hypertension. We highlight redox-sensitive TRPM2 as a putative vascular target in hypertension.
Abstract P174: Loss of Bmal1 in the Collecting Duct Lowers Blood Pressure in Male, but Not Female, Mice
Authors: Zhang Dingguo , Jin Chunhua , Tao Binli , Pollock David M
Published: December 2018

Kidney function follows a 24-hour rhythm that is subject to regulation by so-called circadian clock genes. Previous studies suggested a potential role of circadian gene
Bmal1
in regulating renal excretory function and blood pressure, yet the mechanism is not completely clear. Our lab showed that high salt diet induces a phase shift in
Bmal1
expression in the renal inner medulla that is dependent on endothelin B receptor (ET
B
) function. In addition, the ET
B
receptor-mediated natriuretic effect is time-of-day- and sex-dependent. We recently generated a mouse model that lacks
Bmal1
expression in principal cells of the renal collecting duct, which has the highest concentration of ET
B
receptor. The current study was designed to test the hypothesis that Bmal1 in the collecting duct regulates blood pressure in a sex-dependent manner. Male (n=8-9) and female (n=6) collecting duct
Bmal1
knockout (CD
Bmal1
KO) and floxed control (flox) mice were implanted with telemetry transmitters, and fed normal salt (0.49% NaCl) diet (NS) for 6 days, followed by 6 days of high salt (4% NaCl) diet (HS). After this period, mice were treated with an ET
B
receptor antagonist (A-192621; 30mg/kg/day) for another 6 days. At the end of the study, we performed cosinor analysis on telemetry data collected throughout the study. Under NS, male CD
Bmal1
KO showed significantly lower 24-hr mean arterial pressure (MAP) compared to flox (105±1 vs 112±1 mmHg, p=0.01). However, we did not observe any significant differences in the MAP of female mice (106±1 vs 108±1 mmHg, p=0.26). Under HS, MAP of male CD
Bmal1
KO was significantly lower compared to flox (107±1 vs 114±1, p=0.01). No significant differences were observed in female mice (109±1 vs 110±1 mmHg, p=0.63). In male CD
Bmal1
KO, the increase in MAP in response to the ET
B
receptor antagonist was significantly attenuated compared to flox (124±1 vs 130±1 mmHg, p<0.01). However, the increase in MAP in female mice was not significantly different between CD
Bmal1
KO and flox (130±1 vs 127±2 mmHg, p=0.33) during ET
B
blockade. There were no differences in the amplitude of diurnal MAP between genotype in either sex on any diet. These data suggest that collecting duct Bmal1 plays an important role in blood pressure regulation in male, but not female, mice.
Abstract P181: Hypertension Treatment Disruption During Pregnancy Among Women With Chronic Hypertension
Authors: Chen Lu , Shortreed Susan M , Easterling Thomas , Cheetham T. Craig , Holt Victoria , Avalos Lyndsay A , Walker Rod , Kamineni Aruna , Reynolds Kristi , Dublin Sascha
Published: December 2018

Objective:
In the U.S., 1.3 million women of reproductive age take antihypertensive medications for chronic hypertension. However, some of these medications are considered unsafe during pregnancy. We evaluated the burden of switching and stopping medications during pregnancy among women receiving treatment for chronic hypertension.

Study Design:
We identified a population-based cohort of women with chronic hypertension who received antihypertensive medications within 120 days before pregnancy and gave birth to a singleton between 2005 and 2014 within three Kaiser Permanente regions. We characterized women’s antihypertensive medication use from 120 days before pregnancy through delivery. We ascertained the highest systolic and diastolic blood pressures in the 120 days before the start of pregnancy and supplemented these values with measures up through 8 weeks’ gestation when pre-pregnancy values were missing.

Results:
5,782 pregnant women were included. Prior to pregnancy, the most commonly used medication classes were thiazide diuretics (2,370/5,782, 41%), beta-blockers (1,569/5,782, 27%) and angiotensin-converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs) (1,391/5,782, 24%). In contrast, the predominant medications during pregnancy were labetalol (2,165/5,782, 37%) and methyldopa (1,593/5,782, 28%). During pregnancy, 18% of the cohort (1,037/5,782) had no antihypertensive medication fills. Women taking ACEI/ARBs or thiazides before pregnancy were the most likely to have no medication fills in pregnancy (23% and 20%, respectively). Many women (n=881) had at least one severe high BP (SBP ≥160 or DBP ≥110) before pregnancy, and in this group, 15% (132/881) filled no medications throughout pregnancy.

Conclusion:
Women with chronic hypertension frequently stop antihypertensive medications during pregnancy, even women with a severely high BP documented before pregnancy. Research is needed to understand impact of these treatment interruptions on pregnancy outcomes and women’s long-term health.
Abstract P187: Elevated Resting Heart Rate is Associated With Dyslipidemia in Chinese Rural Population: The Henan Rural Cohort Study
Authors: Zhang Xia , Wang Chongjian , Li Yuqian , Yu Songcheng , Liu Xiaotian , Tu Runqi , Zhang Haiqing , Yang Kaili , Qiao Dou , Liu Xue , Zhang Gongyuan , Mao Zhenxing
Published: December 2018

Aim:
The aim of this study was to explore the association between resting heart rate (RHR) and dyslipidemia in Chinese rural population. Simultaneously, we examined whether this association was mediated by some degree of fasting plasma glucose (FPG).

Methods:
A total of 38727 participants aged 18-79 years were derived from the Henan Rural Cohort Study during 2015-2017 in China. Restricted cubic splines and logistic regression were used to estimate the
OR
s and 95%
CI
s. Mediation analysis using bootstrap was performed to examine the contribution of FPG to RHR-related dyslipidemia.

Results:
The results showed that RHR were associated with the risk of dyslipidemia, and the corresponding adjusted
OR
s (95%
CI
s) for each quartiles were 1.00, 1.12(1.05-1.20), 1.22(1.15-1.30), 1.45(1.36-1.54), respectively. In continuous analysis, each 1SD increment in RHR was significantly associated with a 15% increased risk of dyslipidemia. The restricted cubic splines showed that the risk of dyslipidemia increased gradually with continuous RHR. In mediation analysis, the percentage of excess relative risk mediated for FPG was 24.63%.

Conclusion:
Elevated RHR was significantly associated with the risk of dyslipidemia in Chinese rural population. In addition, RHR -related dyslipidemia was mediated by some degree of FPG. However, the potential clinical application remains to be determined.

Figure
OR
(solid lines) and 95%
CI
(dashed lines) for the risk of dyslipidemia along with the changes of resting heart rate from restricted cubic splines.

Adjusted for age, gender, education level, marital status, smoking, drinking, physical activity, family history of dyslipidemia and body mass index.
Abstract P198: WNK-SPAK-NKCC1 Cascade Activation Contributes to Worsened Brain Damage in Mice With Hypertension Co-Morbidity after Ischemic Stroke
Authors: Bhuiyan Mohammad Iqbal H , Huang Huachen , Zhang Ting , Molyneaux Bradley J , Poloyac Samuel M , Zhang Jinwei , Deng Xianming , Sun Dandan , Sun Dandan
Published: December 2018

Objectives:
The WNK-SPAK/OSR1 kinase complex plays an important role in renal salt handling and pathogenesis of hypertension by regulating ion transporters and channels. Hypertension is the most common risk factor for stroke and stroke patients with hypertension comorbidity have worsened outcome with an increased risk of dependency or death. However, the mechanisms underlying the worsened ischemic stroke pathophysiology with hypertension comorbidity remain poorly defined. In this study, we investigated roles of the WNK-SPAK-NKCC1 signaling pathway in ischemic brain damage in mice with hypertension comorbidity.

Methods:
Hypertension was induced in C57BL/6j male mouse (12-15 weeks) by subcutaneous infusion of 1000 ng/kg/min angiotensin II (AngII, mini-osmotic pump) for two weeks. Permanent ischemic stroke was induced by permanent occlusion of the distal branches of the left middle cerebral artery (pd-MCAO). Brain tissues were harvested for immunoblot assessment of expression levels of NKCC1, SPAK/OSR1 or WNK1-4. Infarct volume and hemisphere swelling were determined by TTC staining, and behavioral deficits were analyzed by foot fault test, cylinder test and adhesive tape removal test.

Results:
pd-MCAO stimulated expression of WNK proteins (isoforms 1, 2, 4), total and phosphorylated SPAK/OSR1 and NKCC1 proteins in ischemic brains of the AngII-infused hypertensive mice compared to normotensive saline controls. In parallel with the increased activation of WNK-SPAK-NKCC1 signaling, hypertensive mice displayed significantly larger infarct volume and hemispheric swelling at 24 h after pd-MCAO compared to normotensive controls. Moreover, hypertensive mice exhibited a slow recovery of neurological function after ischemic stroke compared to normotensive counterparts as assessed by sensory-motor sensitive tests.

Conclusions:
These results suggest that activation of the WNK-SPAK-NKCC1 complex in hypertensive ischemic brains associates, at least in part, with the worsened brain damage and neurological deficits. Pharmacological inhibition of WNK-SPAK complex has therapeutic potentials for stroke therapy with hypertension comorbidity.
Abstract P200: Night Sleep Duration and Hypertension in Chinese Rural Population: The Henan Rural Cohort Study
Authors: Zhang Haiqing , Li Yuqian , Mao Zhenxing , Liu Min , Huo Wenqian , Liu Ruihua , Liu Xiaotian , Tu Runqi , Yang Kaili , Qian Xinling , Jiang Jingjing , Zhang Xia , Tian Zhongyan , Bie Ronghai , Wang Chongjian
Published: December 2018

Aim:
The purpose of the study was to evaluate the association between night sleep duration and hypertension, and to examine whether the mediation effect of night sleep duration and hypertension exists in rural population based on the factors of blood lipids.

Methods:
Night sleep duration was classified into <5h, 5-h, 6-h, 7-h, 8-h, 9-h and ≥10h. Logistic regression and restricted cubic spline were performed to evaluate the association of night sleep duration with hypertension. Mediation analysis was used to explore the mediation effect of night sleep duration and hypertension.

Results:
Among the 37, 317 participants, a total of 12, 333 suffered from hypertension. Compared with reference, fully-adjusted
OR
of hypertension, undiagnosed and diagnosed hypertension were 1.52(1.25-1.84), 1.68(1.32-2.14) and 1.32(1.03-1.69) respectively among male sleeping for 10h at night. Additionally, the dose-response relationship of night sleep duration with prevalent hypertension risk was also found in male (Figure 1,
P
<0.05). Mediation analyses showed that the
OR
for hypertension among male (total effect, 1.089;
95% CI
, 1.040, 1.139). Low density lipoprotein cholesterol (LDL-C) showing the
OR
, 1.003(95%
CI
, 1.001, 1.005) for indirect effect and 1.085(1.038, 1.137) for direct effect partly mediated their association.

Conclusion:
A dose-response association of night sleep duration and hypertension was found in male but not in female. Additionally, LDL-C mediated the association between night sleep duration and hypertension among male.

Figure 1. Relation of night sleep duration for hypertension from restricted cubic splines.
Abstract P208: Association of Baseline Medication Burden With Blood Pressure Control, Patient-Reported Outcomes, and Serious Adverse Events: Findings from the SPRINT Trial
Authors: Derington Catherine G , Gums Tyler H , Bress Adam P , Herrick Jennifer S , Greene Tom H , Moran Andrew E , Kronish Ian M , Morisky Donald E , Trinkley Katy E , Saseen Joseph J , Reynolds Kristi , King Jordan B
Published: December 2018

Background:
Achieving intensive systolic blood pressure (SBP) control (<120 mmHg) requires more antihypertensive medications than standard control (<140 mmHg). It is unclear how total medication burden impacts hypertension outcomes.

Objective:
To evaluate the association of total medication burden at baseline and SBP control, serious adverse events (SAEs), medication adherence, and treatment satisfaction in the Systolic Blood Pressure Intervention Trial (SPRINT).

Methods:
Baseline medication data were obtained by pill bottle review at randomization and categorized as high (≥ 5 prescription medications) vs low (< 5 medications) medication burden. SBP control per randomization goal, eight item Morisky Medication Adherence Scale (MMAS 8), and Treatment Satisfaction Questionnaire were evaluated at 1-year. SAEs were collected over the trial. We calculated adjusted risk ratios (RR) and hazard ratios (HR) for each outcome associated with medication burden using multivariable regression models stratified by randomized group.

Results:
Among 8454 participants with available data at 1-year follow up, 4797 (57%) and 3657 (43%) had high and low medication burden, respectively (mean medications ± SD; 8 ± 3 vs 3 ± 1). High medication burden was associated with reduced SBP control in the intensive arm (RR, 95%CI; intensive 0.92, 0.87-0.98; standard 0.98, 0.94-1.03; interaction p 0.01) and increased SAEs in both arms (HR, 95%CI; intensive 1.57, 1.40-1.77; standard 1.59, 1.41-1.78; interaction p 0.54). High medication burden was associated with worse medication adherence in the intensive arm and improved adherence in the standard arm (RR for MMAS 8 ≥6, 95%CI; intensive 0.97, 0.94-1.00; standard 1.05, 1.02-1.09; interaction p <0.01). High medication burden was not associated with hypertension treatment satisfaction (RR for satisfied/very satisfied, 95%CI; intensive 0.99, 0.98-1.00; standard 0.98, 0.97-1.00; interaction p 0.50).

Conclusion:
In SPRINT, high medication burden at baseline was associated with higher risk of SAEs. The association of high medication burden on the likelihood of achieving SBP goal and medication adherence at 1 year was different by treatment arm; medication burden was not associated with hypertension treatment satisfaction.
Abstract P210: Blood Pressure Medication Adherence Among Medicare Beneficiaries, Causes and Consequences
Authors: Aitken William , Bakhos Lara
Published: December 2018

Introduction:
Medication non-adherence is a major healthcare barrier, especially among diseases which are largely asymptomatic such as hypertension. The impact of poor medication adherence ranges from patient specific adverse health outcomes to broader strains on health care system resources. Accordingly, there is rich literature examining the causes and consequences of suboptimal medication adherence.

Objective:
To document the relationship between blood pressure medication adherence, socioeconomic status, health care costs, and outcomes among Medicare beneficiaries with heart disease in the United States.

Methods:
The CDC Wonder database was used to retrieve Centers for Medicare and Medicaid Services’ data pertaining to blood pressure medication adherence, socio-economic variables, per-capita healthcare costs, and cardiovascular outcomes among beneficiaries by county across the United States. Spearman correlation was used to analyze the relationship between various factors.

Results:
Among Medicare beneficiaries, blood pressure medication non-adherence rates ranged from 15.9% to 56.2% with a mean of 26.5% ± 5.3% among the 3,196 counties reporting data. Factors that strongly correlated with non-adherence include poor educational attainment (0.678, p<0.01) and poverty status (0.613, p<0.01). Although non-adherence had a weakly positive relationship with inpatient costs (0.183, p<0.01) and total overall costs (0.324, p<0.01), it demonstrated a solid correlation with cardiovascular deaths (0.42, p<0.01), stroke death (0.420, p<0.01), stroke hospitalization (0.415, p<0.01), and hypertension related hospitalization (0.561, p<0.01).

Conclusions:
Our analysis of Medicare beneficiary data across the United States demonstrates a strong correlation between socioeconomic determinants of health and poor medication adherence. Our data further demonstrates that poor medication adherence translates into both worse cardiovascular outcomes and higher health care costs. In an era where health care spending has become overwhelmingly problematic, these findings provide compelling evidence for increased efforts focusing on educational and incentive based programs to improve medication adherence.
Abstract P217: Evidence for Impaired Diurnal Cardio-Vagal Tone Due to p67phox in Dahl Salt-Sensitive Rats
Authors: Becker Bryan K , Chen Daian , Colson Jackson C , Jin Chunhua , Cowley Allen W , Geurts Aron , Young Martin E , Pollock Jennifer S , Pollock David M
Published: December 2018

Salt-sensitive hypertension is associated with increased reactive oxygen species (ROS) generation and sympathetic tone, and diurnal alterations in the rhythm of blood pressure control further increase cardiovascular disease risk. However, the interaction between ROS and diurnal autonomic rhythms is unclear. We hypothesized that ROS generation impairs diurnal autonomic tone in the Dahl salt-sensitive model of hypertension. Dahl salt-sensitive (Dahl SS; n=14), Dahl SS p67phox null (SSp67; n=8), and Dahl SS with an introgressed chromosome 13 from Brown-Norway (SS.BN13; n=7) rats were instrumented with telemetry transmitters and fed a normal (0.4% NaCl), low (0.04% NaCl), or high salt (4.0% NaCl) diet. Data were analyzed on days 7 - 10 of each diet. SSp67 and SS.BN13 have lower blood pressure than Dahl SS on high salt diet. Surprisingly, we saw no difference between groups in 24-hr heart rate or systolic blood pressure low frequency to high frequency (LF/HF) on each diet suggesting a similar 24-hr autonomic tone across genotypes. However, SSp67 had a reduced LF/HF amplitude (day-night) compared to Dahl SS during high salt (0.36 ± 0.05 vs. 0.67 ± 0.11 LF/HF; respectively p=0.01). SSp67 also had higher 24-hr root mean squared of successive differences (RMSSD), a marker of cardio-vagal tone, within each salt diet (table). Also, RMSSD amplitude was higher in SSp67 (table) than other groups within each salt diet. These results support the hypothesis that reductions in cardio-vagal tone and diurnal autonomic function in the Dahl SS rat is due to NADPH oxidase activity, most likely via production of ROS. Inhibition of ROS may be an effective therapy to improve diurnal cardio-vagal tone.
Abstract P218: Downregulation of Renal Tumor Necrosis Factor-Alpha Production in Response to Hypotonic Stress Facilitates Adaptive Increases in Renal Cortical Angiotensinogen and Nkcc2b
Authors: Hao Shoujin , Salzo Joseph , Hao Mary , Ferreri Nicholas R
Published: December 2018

We previously showed that diverse stimuli activate the thick ascending limb of Henle’s loop (TAL) to synthesize tumor necrosis factor-alpha (TNF), which subsequently acts as an endogenous inhibitor of the Na(+)-K(+)-2Cl(-) cotransporter (NKCC2). Moreover, renal-specific silencing of TNF unmasks salt-dependent increases in blood pressure via a mechanism involving NKCC2A. The objective of the present study was to determine the effects of TNF on NKCC2 isoform and angiotensinogen (AGT) expression in the renal cortex under conditions of hypotonic stress. Mice given a low salt (0.02% NaCl) diet (LS) for 7 days exhibited a 62±7.4% decrease (p<0.5, n=4) in TNF mRNA expression in the renal cortex, compared with mice ingesting a normal salt diet (NSD), which was associated with a concomitant 4-fold increase in renal cortical AGT mRNA accumulation (p<0.05, n=4). Mice ingesting LS also exhibited about a 63% increase (p<0.05, n=4) in cortical TAL phospho-NKCC2 (pNKCC2) expression and a 3-fold increase in NKCC2B mRNA abundance without a concurrent change in NKCC2A mRNA accumulation. The increases in AGT and NKCC2B mRNA abundance were increased by 6-fold (p<0.05, n=4 ) and 5-fold (p<0.05, n=4), respectively, in mice ingesting LS that also received an intrarenal injection of a lentivirus construct designed to specifically silence TNF in the kidney (U6-TNF-ex4) compared with mice injected with control lentivirus (U6). The effects of a single intrarenal injection of murine recombinant TNF (5ng/g body weight) or saline control for 24 hr on renal AGT and NKCC2 mRNA levels were then determined in mice that ingested LS for 7 days. Administration of TNF inhibited the increase of AGT and NKCC2B mRNA abundance by approximately 42±5.9% and 49±6.5% respectively, p<0.05, n=4 ) in mice exposed to hypotonic stress. Similarly, intrarenal injection of TNF inhibited the increase in pNKCC2 by approximately 54% (p<0.05, n=4 ) in renal cortex from mice given LS for 7 days. Collectively, these findings suggest that downregulation of renal TNF production in response to hypotonic conditions contributes to the regulation of sodium chloride reabsorption via adaptive increases in AGT as well as a selective effect on NKCC2B, which is exclusively expressed by macula densa cells in the renal cortex.
Abstract P230: Food Insecurity is Associated With Hypertension in Children and Adolescents Independent of Obesity
Authors: South Andrew M , Palakshappa Deepak , Brown Callie
Published: December 2018

Background:
Food insecurity (FI), the limited or uncertain availability of nutritionally adequate foods, affects 40 million Americans and is an under-recognized contributor to health disparities, especially in children and adolescents. FI can lead to poor diet quality, including increased salt intake, and therefore may be a risk factor for hypertension and cardiovascular disease. While a link between FI and cardiovascular disease has been suggested in adults, this relationship in children is unknown, especially within the U.S.

Objective:
To determine if a relationship exists between FI and high BP in a nationally representative cohort of children and adolescents.

Design and Methods:
We performed a cross-sectional analysis of data from children aged 8-17 years in the National Health and Nutrition Examination Survey (NHANES), 2007-2014. FI was assessed using the USDA Food Security Survey Module. BP was measured three times and averaged. We defined high BP as i) SBP or DBP ≥90
th
%ile for age <13 years or ≥120/80 mmHg for age ≥13 years; ii) reported diagnosis of hypertension; or iii) reported current use of an antihypertensive medication. Using measured height and weight, we categorized weight status based on BMI. We used multivariate logistic regression models to determine the association between FI and high BP, controlling for age, sex, race, and BMI category. All analyses accounted for the complex survey design of NHANES including survey weights, clustering, and stratification.

Results:
FI was present in 20.5% (1,460 of 7,125) of subjects and 12.4% (883 of 7,125) had high BP. On bivariate analysis high BP was more common among those with FI (14.4%, 1,026 of 7,125) than those who were food secure (11.6%, 826 of 7,125,
p
=0.001). After controlling for potentially confounding factors, FI remained associated with high BP (OR 1.25, 95% CI 1.04-1.50).

Conclusions:
We found that FI was associated with an increased likelihood of high BP in a large, nationally representative cohort of U.S. children and adolescents independent of obesity. FI likely has a significant impact on health and cardiovascular disease during childhood, so efforts to address FI will also help reduce the burden of cardiovascular disease in children and in later adulthood.
Abstract P235: Altered Brain-Gut-Lung Axis in Hypoxia-Induced Pulmonary Hypertension
Authors: Oliveira Aline C , Sharma Ravindra K , Yang Tao , Aquino Victor , Lobaton Gilberto O , Bryant Andrew J , Richards Elaine M , Raizada Mohan K
Published: December 2018

Background:
Recent evidence indicate that gut microbiota plays important role in pathogenesis and progression of chronic lung diseases such as asthma, respiratory infections and COPD. However, implications of this gut-lung communication and involvement of peripheral and neural immune system in pulmonary hypertension (PH) remains unknown.

Objective:
Investigate the hypothesis that increased activation of microglial cells, autonomic nervous system, altered gut pathology and gut microbiota are associated with PH suggesting a dysfunctional brain-gut-lung axis in PH pathology.

Methods:
C57BL/6 (WT) male mice were exposed to chronic hypoxia (10%O2) or Normoxia for 4 weeks in a ventilated chamber (n=5-8/group). Millar pressure catheter was used to measure pulmonary hemodynamics, Iba1 specific antibody for immunohistochemical analysis of microglial cells and fecal 16S rDNA for gut microbiota analysis.

Results:
Hypoxia induced a 77% increase in right ventricular (RV) systolic pressure (RVSP: N:19.5 ± 2 mmHg Vs H:33.7 ± 2, p<0.001) and RV hypertrophy (RVH: N: 0.139 ± 0.09 Vs H: 0.192± 0.008). This was associated with substantial enhancement in sympathetic activity (LF/HF: N:0.23 ± 0.8 mmHg Vs H: 1.19 ± 0.08, p<0.001) and increase in number of microglial cells in autonomic brain regions, predominantly the paraventricular nucleus of hypothalamus. Characteristics of gut pathology such as ~50% increase in fibrotic area and muscularis layer thickness and significantly decreased villi length and number of goblet cells in small intestine were also observed. Also, principal coordinate analysis of the bacterial composition profile showed a clear separation and clustering of bacterial genera of hypoxic and normoxic mice (ANOSIM p<0.001).

Conclusions:
(I) Hypoxia-induced pulmonary and cardiac pathophysiology is associated with increased microglia in cardiorespiratory-relevant areas and enhanced sympathetic activity. (II) Fibrotic area and muscularis layer thickness increased while villi length and number of goblet cells decreased in gut (III) gut microbiota are altered. Together, these observations indicated an altered brain-gut-lung axis in PH.
Abstract P242: Effects of Proton Receptor Gpr4 Deficiency on Angiotensin Receptors in Kidney and Hindbrain
Authors: Petrovic Snezana , Tommasi Ellen , Sun Xuming , Diz Debra I
Published: December 2018

The proton receptor GPR4, a G protein-coupled receptor with protons as ligands, is abundant in the brain [subfornical organ (SFO) and paraventricular nucleus (PVN) of the hypothalamus], lung, and kidney. The receptor is activated in physiological pH range and GPR4 deletion is associated with chronic mild acidosis. The GPR4-/- mice exhibit ~15 mm Hg lower systolic blood pressure accompanied by ~50% lower angiotensin lower AT
1
receptors in SFO and PVN. We now report data for angiotensin receptor binding in the kidney and hindbrain using
in vitro
receptor autoradiography with
125
I-Sarthran as the ligand in GPR4-/- (n = 3 kidney, n = 4 hindbrain) and wild type (GPR4+/+, n = 3 kidney, n = 4 hindbrain) mice. GPR4-/- mice have lower
125
I-Sarthran specific maximal binding in the renal medullary region (43 ± 16 vs. 127 ± 20 fmol/mg protein in GPR4+/+; p = 0.03), which is the region with highest expression of GPR4. There was a trend for lower binding, although not significant, in the vasa recta area (78 ± 17 vs. 177 ± 46 fmol/mg protein in GPR4+/+; p = 0.12), glomeruli (414 ± 48 vs. 522 ± 17 fmol/mg protein in GPR4+/+; p = 0.10) and tubules (250 ± 44 vs. 350 ± 28 fmol/mg protein in GPR4+/+; p = 0.13). There were no differences in binding maximal density in brain medullary regions such as nucleus tractus solitarii (NTS), area postrema (AP), dorsal motor nucleus of the vagus (DMV) or olivary complex (OC). Non-specific binding was similar in GPR4+/+ and -/- mice in both kidney and brain. AT
1
receptors as defined by competition with losartan account for the majority of binding in each of the regions in mouse kidney (>70%), while the brain medullary binding exhibits ~50% AT
1
and AT
2
sites. Thus, GPR4 deletion lowers AT
1
receptors in tissues involved in control of blood pressure and fluid and electrolyte balance, such as forebrain nuclei and renal medullary regions where there is high abundance of both AT
1
and GPR4 receptors. Whether the down-regulation of the AT
1
receptor at these sites is a direct effect in response to loss of activation of the GPR4 or is secondary to the acid-base balance alterations in these animals is unknown. However, the lower blood pressure in the GPR4-/- mice supports the concept that the GPR4 receptor is a potential therapeutic target for lowering of pressure.
Abstract P248: Overexpression of an Intracellular Angiotensin II Fusion Protein Selectively in the Mitochondria of Mouse Proximal Tubule Cells Induces Mitochondrial Stress and Glycolytic Responses: Roles of Nitric Oxide and Superoxide
Authors: Li Xiao C , Cook Julia L , Zhuo Jia L
Published: December 2018

Endocrine and paracrine angiotensin II
(
ANG II) activates cell surface AT
1
receptors to induce mitochondrial superoxide (O
2
-
) production and uncoupling of eNOS, leading to ANG II-induced renal and hypertensive injury. Little is known, however, whether ANG II is internalized to the mitochondria to activate AT
1
or AT
2
receptors. We tested the hypothesis that ANG II in the mitochondria exerts important dual roles on mitochondrial stress and glycolytic responses via the AT
1a
/NADPH oxidase/O
2
.-
and AT
2
/eNOS/NO signaling pathways. To test the hypothesis, a mitochondria-targeting ANG II protein (mito-ECFP/ANG II) was expressed selectively in the mitochondria of mouse proximal tubule cells, and treated with or without AT
1
receptor blocker losartan (10 μM), AT
2
receptor blocker PD123319 (10 μM), a non-selective NOS inhibitor L-NAME (10 mM), or a scavenger of mitochondrial superoxide, mito-TEMPO (10 μM) for 48 h, respectively. The mitochondrial stress and glycolytic responses were then determined using Seahorse XF
e
24 Extracellular Flux Analyzer. Expression of mito-ECFP/ANG II alone significantly increased oxygen consumption rate (OCR) (Control: 259.8 ± 52.2 vs. mito-ECFP/ANG II: 512.5 ± 75.6 pmol/min;
p
<0.01, n=8) and extracellular acidification rate (ECAR) (Control: 13.5 ± 2.2 vs. mito-ECFP/ANG II: 19.3 ± 2.4 mpH/min;
p
<0.01, n=8), respectively. These mito-stress responses were blocked by losartan (
p
<0.01, n=8), but not by PD123139 (
n.s.
). Furthermore, the mito-stress response of mito-ECFP/ANG II was significantly attenuated by mito-TEMPO (288.1 ± 10.3 pmol/min;
p
<0.01, n=8), and augmented by L-NAME (623.5 ± 8.7 pmol/min,
p
<0.05, n=8). Finally, the mito-stress response to mito-ECFP/ANG II expression was associated with significant increases in mitochondrial redox carries, Complex I (NADH coenzyme Q reductase), Complex II (succinate dehydrogenase), Complex III (cytochrome

bc
1

complex) and Complex IV proteins (cytochrome c oxidase) (
p
<0.01). We concluded that ANG II in the mitochondrial induces important mitochondrial stress and glycolytic responses primarily via the AT
1a
/NADPH oxidase/O
2
.-
signaling pathways in mouse proximal tubule cells.
Abstract P262: Repression of Genes Involved in Fatty Acid Metabolism during Acute Renal Failure
Authors: Shahid Mohd , Kishta Lina , Mdanat Dana , Yousefipour Zivar , Newaz Mohammed
Published: December 2018

Peroxisome proliferator-activated receptors (PPARs) are highly expressed in the kidney, but their role in acute renal failure (ARF) remains elusive. Previously, we have shown PPARγ-ligand attenuated renal injury and improved renal function in ARF. In this study, we explored specific downstream targets of PPARγ that may be involved in reno-protection. Male Sprague-Dawley rats (250-300 gm) were randomly divided into two groups, control, and ARF: where they received GW1929 (PPARγ ligand), apocynin (NADPH oxidase inhibitor), or vehicle. After 7 days of pretreatment, ARF was induced by injecting glycerol (50% v/v, 8 ml/kg; i.m.). After 24 hours, blood and kidneys were collected and processed for mRNA extraction. The expression of PPARγ-responsive genes was determined by a PCR array using qRT-PCR. Markers for renal injury and oxidative stress and NADPH oxidase activity were determined by ELISA. The data revealed that fatty acid (FA) transporter genes (
Slc27a2, ApoE
, FABP2, FABP3,
and
CD36
)
, were strikingly suppressed (>100-folds, p<0.001) in ARF compared to control. Genes involved in FA metabolism such as
FABP
, PGC1α, Cpt1b, Creb1
were also markedly inhibited (>20-folds, p<0.001). In addition, expressions of key survival genes
PCK2, Pten
, Crebbp
, and
SRC
, were concurrently diminished (>25-folds, p<0.001). However, this attenuation was restored to normal levels with GW1929 treatment. Pretreatment with GW1929 reduced the activity of KIM1 (14.8±1.5 vs. 18.7±0.3 ng/μg; p<0.05) and NGAL (129±6 vs. 233±5 ng/μg; p<0.01), isoprostane levels (73.3±3.7 vs. 110±8 pmol/mg), and NADPH oxidase activity (0.96±0.04 vs. 1.7±0.04 nmol/mg protein), indicating reversal of renal injury and oxidative stress. Interestingly, apocynin treatment also inhibited ARF-induced downregulation of genes involved in FA metabolism and growth signals, demonstrating the ROS-dependency of ARF-induced repression of PPARγ-responsive genes. As expected, apocynin reduced isoprostane levels but did not impact KIM1 expression in ARF, suggesting no improvement in glomerular injury with this treatment. Collectively, the data suggest that renal damage in ARF is preceded by impairment in FA metabolism and growth signals via a ROS-dependent manner.
Abstract P264: Ghrelin-Induced Sodium Reabsorption is Mediated by PKA and a Microtubulin-Dependent Network In Rats
Authors: Kemp Brandon A , Howell Nancy L , Padia Shetal H
Published: December 2018

Previous studies have shown that intrarenal ghrelin infusion activates ghrelin receptors in the collecting duct to increase αE
Na
C-dependent sodium (Na
+
) reabsorption
in vivo
, but the underlying mechanisms are unknown. 72h following uninephrectomy, 12-week-old female Sprague-Dawley rats received the following renal interstitial (RI) infusions for 1h after a 1h control period in which they received RI infusions of vehicle (5% dextrose in water, D
5
W): (1) vehicle (N=7), (2) ghrelin (3 μg/min, N=6), (3) ghrelin + PI3K inhibitor, LY-294002 (0.1 μg/kg/min, N=6), (4) LY-294002 alone (N=4), (5) ghrelin + PKA inhibitor, Rp-cAMPS (10 μg/kg/min, N=7), (6) Rp-cAMPs alone (N=5), (7) ghrelin + microtubule polymerization inhibitor nocodazole (3 μg/kg/min, N=7), (8) nocodazole alone (N=6), (9) ghrelin + actin polymerization inhibitor, cytochalasin D (0.3 μg/kg/min, N=6), and (10) cytochalasin D alone (N=6). Compared to baseline, RI ghrelin significantly decreased U
Na
V to 52.2 ± 9.9% (P<0.001), but this effect was abolished during concomitant PKA and microtubulin inhibition (128.6 ± 15.9% and 123.5 ± 12.2%, respectively, both P<0.01 from ghrelin alone). Ghrelin-induced antinatriuresis persisted in the presence of PI3K and actin inhibition (62.2 ± 4% and 59.7 ± 10.8% respectively, both P<0.01 from baseline and P=NS from ghrelin alone). RI infusion of inhibitors alone had no effect on U
Na
V compared to vehicle and mean arterial pressures did not change following any RI infusion. Taken together, these studies highlight the importance of PKA and microtubulin polymerization in αE
Na
C-mediated Na
+
reabsorption.
Abstract P274: Endothelial Dysfunction of Conduit Arteries in Amyloid Precursor Protein-Deficient Mice
Authors: d'Uscio Livius V , Katusic Zvonimir S
Published: December 2018

Amyloid precursor protein (APP) is an integral membrane protein expressed in the peripheral arteries. However, the exact vascular physiological function of APP is unknown. Male APP-deficient (APP
–/–
) and their wild-type littermates (WT) mice were used to characterize the phenotype of APP in the control of vascular function. Isometric force of isolated aortic rings was recorded in organ chambers. Circulating levels of norepinephrine and epinephrine were significantly enhanced in APP
–/–
mice (4723±566 pg/mL and 854±98 pg/mL, respectively P<0.05 vs. WT: 1999±319 pg/mL and 429±71 pg/mL, respectively; n=13). The efficacy of phenylephrine induced contractions were significantly reduced in the aorta of APP
–/–
mice (21±3%, P<0.05 vs. WT: 47±4%; n=10) while contractions to prostaglandin F
2α
were unchanged (135±4%, P=n.s. vs. WT: 133±3%; n=9). Western blot analysis revealed that protein expression of alpha1D adrenergic receptors was significantly downregulated in APP
–/–
mice aortas (0.21±0.05 O.D.; P<0.05 vs. WT: 0.48±0.11 O.D.; n=6). In contrast, endothelium-dependent relaxations to β-agonist isoproterenol were significantly enhanced in APP
–/–
mice aortas (P<0.05; n=10) while endothelium-dependent relaxations to acetylcholine were unaltered (P=n.s.; n=12). Incubation of aortic rings with indomethacin significantly impaired relaxations to isoproterenol as well as acetylcholine in APP
–/–
mice (P<0.05; n=8) while concomitant treatment with NOS inhibitor L-NAME completely abolished relaxations to both agonists (P<0.05; n=6-7). Incubation of aortic rings with isoproterenol significantly increased cAMP in the aortas of APP
–/–
mice (16.2±4.1 pmol/mg; P<0.05 vs. WT: 6.6±4.1 pmol/mg; n=7). Furthermore, cAMP levels were significantly enhanced by acetylcholine in APP
–/–
mice aortas (38±9 pmol/mg; P<0.05 vs. WT: 14±3 pmol/mg; n=8) while acetylcholine stimulated cGMP levels were reduced (59±5 pmol/mg; P<0.05 vs. WT: 83±7 pmol/mg; n=12). Our results suggest that increased circulating levels of catecholamines in APP
–/–
mice are responsible for observed vascular phenotype. These findings indicate that under physiological conditions, APP expression plays an important role in control of vascular endothelial function
.
Abstract P282: Knockout of Transient Receptor Potential Ankyrin 1 Exacerbates Renal Ischemia-Reperfusion Injury
Authors: Ma Shuangtao , Wang Donna H
Published: December 2018

Transient receptor potential ankyrin 1 (TRPA1) is a newly identified oxidant sensor and has anti-oxidative properties. The role of TRPA1 in acute kidney injury is largely unknown. In this study, we test the hypothesis that dysfunctional TRPA1 leads to aggravated renal inflammation and injury after renal ischemia-reperfusion injury using Trpa1 gene knockout and wild-type mice. Male 8-week-old mice were subjected to renal ischemia for 30 minutes by clamping bilateral renal pedicles under isoflurane anesthesia; the mice were sacrificed at 24 hours after surgery. Renal functional impairment, tubular injury, oxidative stress, and renal inflammation were measured at 24 hours after reperfusion. TRPA1 was found to be expressed in the kidney of wild-type mice and significantly downregulated after ischemia-reperfusion injury (p<0.01). In Trpa1 knockout mice, plasma creatinine (1.58±0.08
vs.
1.19±0.07 mg/dl, p<0.01) and blood urea nitrogen (171.1±6.5 vs. 143.2±3.9 mg/dl, p<0.01) levels after ischemia-reperfusion injury were significantly higher than those in wild-type mice. Similarly, tubular injury score, calculated based on hematoxylin- and eosin-stained kidney sections, was significantly elevated in Trpa1 knockout mice compared with wild-type mice (p<0.05). Dihydroethidium-stained sections showed that superoxide production was enhanced in Trpa1 knockout mice than wild-type mice after ischemia-reperfusion injury (p<0.01). In renal injured mice, immunofluorescence staining showed that F4/80-positive macrophages were elevated in Trpa1 knockout mice than wild-type mice (p<0.01). Moreover, inflammatory cytokines, including tumor necrosis factor-alpha, interleukin-1β, and interleukin-6 in the kidneys, were increased in Trpa1 knockout mice compared to wild-type mice (all p<0.05). These results show that knockout of TRPA1 exacerbates renal oxidative stress, inflammation, and injury after ischemia-reperfusion, indicating that dysfunctional TRPA1 may lead to impaired protective mechanisms for the kidney while TRPA1 activation may serve as therapeutic means preventing renal injury.
Abstract P284: Increased Blood Pressure in Interleukin-6 Infused Mice is Secondary to Reduced Urinary Sodium Excretion and Not Vascular Dysfunction
Authors: Hecht Gillian G , McCarthy Cam G , Wenceslau Camilla F , Moyer Hayley C , Krishnamurthy Ashwini , Webb R. Clinton , Hoover Robert S , Wynne Brandi M
Published: December 2018

Hypertension (HTN) is associated with increased renal sodium (Na
+
) reabsorption, vascular and endothelial dysfunction and an increase in cytokines, such as interleukin 6 (IL-6). We have previously shown that IL-6 increases blood pressure (BP), and increases the expression/activity of distal nephron Na
+
transport proteins via the mineralocorticoid receptor. We hypothesized that IL-6 increases Na
+
reabsorption, and induces endothelial dysfunction, leading to HTN. All mice were fed high salt food, and osmotic minipumps were implanted containing IL-6 (16 ng/hr, 0.01% BSA/saline), or vehicle/sham surgery (Ctl). To allow for early urine collection, IL-6 infusion was delayed by adding catheters to the minipumps during metabolic cage studies. Tail cuff plethysmography was used to measure systolic BP. Concentration response curves (CRC) to phenylephrine (Phe) and acetylcholine (ACh) were performed on aorta (Ao) and mesenteric arteries (Mes) from IL-6 or Ctl mice. IL-6 infused mice had increased BP by day 3 (D3), as compared to Ctl. Total urine volume (U
Vol
) on D1 of infusion was reduced in IL-6 mice (U
Vol
17.3±4
vs.
29.5±3 mL/day/per 100g body weight (BW); p<0.05), as compared to Ctl. This corresponded with a reduction in total urinary Na
+
excretion (U
Na
81±19 IL-6
vs
. 139±13 mg/day/BW Ctl; p<0.05). By D2, no differences in U
Na
were observed, and by D3 U
Na
levels were increasing in IL-6 infused mice. Similar trends for U
Vol
were observed. These results corresponded with our observed increases in BP. CRCs (D3) to Phe were not changed in Ao. However, Mes from IL-6 mice exhibited a surprising reduction in Phe-mediated contraction (136±7%
vs.
155±5%; p<0.05), compared to Ctl. Similarly, Mes from IL-6 mice exhibited an increase in ACh-mediated relaxation responses (EC
50
-7.5±0.12
vs
. -6.9±0.15; p<0.05). These data suggest that IL-6 increases BP via an early (D1) reduction in U
Na
/U
Vol
, followed by steady state recovery and pressure natriuresis (D3). Additionally, the increased relaxation and reduced contractility observed in the resistance arteries may suggest a compensatory response to the increased BP. Together, our studies suggest that in the early stages of HTN, cytokines may cause changes in renal Na
+
reabsorption via activation of distal Na
+
transporters.
Abstract P288: Bortezomib Reduces Blood Pressure and Proteinuria in the Dahl Salt Sensitive (S) Rat
Authors: Maeda Kenji J , Taylor Erin B , Ross Courtney A , Ryan Michael J , Garrett Michael R , Sasser Jennifer M
Published: December 2018

Hypertension is a major health care disorder affecting up to one in three adults in the United States and is a major risk factor for multiple diseases including coronary artery disease, stroke, congestive heart failure, and end-organ damage. Previous studies have proposed that hypertension is partly driven by an increase in autoantibodies and immunological changes that lead to increased blood pressure. In this study, we tested the hypothesis that treatment with Bortezomib (BTZ), a proteasome inhibitor approved for the treatment of multiple myeloma and mantle cell lymphoma, would attenuate the increase in blood pressure and accompanying rise in urinary protein excretion in the Dahl S and Angiotensin II (Ang II) infused Sprague Dawley (SD) rat models of hypertension. Telemetry implants were placed in the femoral artery for continuous monitoring of mean arterial pressure (MAP) in male Dahl S and SD rats (~14 weeks old, maintained on a normal salt diet), and rats were allowed to recover for one week before baseline urine and MAP were collected. Then, Ang II (400ng/kg/hr) osmotic mini-pumps were implanted in SD rats, and BTZ treatment (0.2 mg/kg twice weekly, s.c.) was started in both Dahl S and SD rats. Ang II mini-pumps were replaced at 2 weeks, and urine was collected at weeks 2 and 4. MAP was reduced by BTZ in Dahl S rats, but no effect was observed in control or Ang II treated SD rats (Table 1). BTZ had no effect on urinary protein excretion (Bradford assay) in any group. These data show that administration of Bortezomib attenuates hypertension in Dahl S but not Ang II hypertension.