bluuebunny/crossref_metadata_2025 huggingface dataset:
Abstract P120: Down Regulation of Add3 in Astrocytes Induces Pro-inflammatory and Fibrotic Factors and May Contribute to Alzheimer’S-related Dementias
Authors: Mims Paige N , Shekhar Sheshank , Wang Shaoxun , Travis Olivia , Fan Fan
Published: March 2022

We genetically mapped a mutation in Add3 in FHH rats that decreases Add3 expression in various tissues, including brain and cerebral vessels, and further decreases with age in comparison with FHH.1
BN
congenic rats in which Chr. 1 from BN rats containing 15 genes, including Add3, was transferred onto FHH genetic background. More recently, we demonstrated that Add3 dysfunction contributes to cerebral vascular impairments in FHH rats, and they exhibit BBB leakage and neurodegeneration after the development of hypertension. In addition, Aβ protein expression in the brain in FHH rats is increased as early as 8 weeks of age. Reactive astrogliosis is a common finding in neurodegenerative diseases and activated astrocytes promote neurodegeneration. Moreover, astrocyte dysfunction affects Aβ clearance and Aβ accumulation is a well-defined feature of Alzheimer’s disease. To further explore whether astrocytes contribute to neurodegeneration and cognitive impairments in FHH rats, we knocked down Add3 expression using Add3 Dicer-substrate RNAi (DsiRNA) in human astrocytes and found that GFAP and IL-6 expression was markedly enhanced in comparison to scramble siRNA treated cells using a q-PCR array. Moreover, the expression of TGF-β2 and TGF-β3 was elevated by 2.0 ± 2.9 and 1.8 ± 1.8 folds, respectively, in Add3 DsiRNA treated astrocytes. In addition, the actin cytoskeleton was disrupted in Add3 DsiRNA treated astrocytes. We found that FHH rats exhibit a reduction in neuronal density and neuronal size in the hippocampus following the induction of hypertension with DOCA/salt. This was associated with loss of capillary density (22.7 ± 0.001% in FHH and 9.6 ± 0.014% in FHH.1
BN
, n = 7 and 9, respectively) and greater expression of GFAP positive astrocytes and loss of neurons in affected areas. Hypertensive FHH rats took 2.5 times longer to escape from an eight-arm water maze as compared to control strains. These results suggest that down regulation of Add3 in astrocytes disrupts the actin cytoskeleton to induce reactive astrogliosis and release of pro-inflammatory and fibrotic factors, which promotes inflammation

and disrupts Aβ uptake, all of which may contribute to neurodegeneration and cognitive deficit associated with aging and hypertension in FHH rats.
Abstract P121: Dipper Pattern and Albuminuria in Controlled and Uncontrolled Hypertensive Patients
Authors: Dinamarco Nelson , Ibiapino Mateus K , Monteiro Gabriela T , Carvalho Barbara E , Sampaio Bernardo P , Carvalho Vanessa B , Dinamarco Marileide , Plavink Frida L
Published: March 2022

BP assessed by ABPM is better related to TOD than office measurement. Evaluate TOD patients presented at a Hypertension Lab for first screening.

Methods:
278 hypertensive (147 Female, aged 19-89) by 24h-ABPM (SpaceLabs 90307), lab. tests, LVMI by Echo (Terason M3000); Divided in two groups: Controlled [C] by 24h-BP (<130x80 mmHg) and Not controlled [NC] (>130/80 mmHg), albuminuria (ALB) was log transformed in order to allow proper analysis. Dipping pattern 24h-ABPM: dipper (DP) (>10- 20%), nondipper-absente (NDP) (<10%), reverse dipper (RDP)(> 20%).

Results:
Table 1 and 2 : Demography and ALB,LVMI. No differences detected in lab panel, except Glu, Trygl, ALB and LVMI.

Discussion:
Expected Higher LVMI, Glu, trygl, ALB levels, in NC group, with significant statistical differences comparing C group. Expected reverse dipping pattern would show differences when compared with dipper pattern but probably the small number of subjects didn’t allow detect such differences.

Conclusion:
Screening with 24-h ABPM is a valuable tool to hypertensives and dipper pattern should be achived to prevent TOD progression.
Abstract P124: Role of Add3 Dysfunction in Renal Epithelial Cells in the Development of Renal Injury in Fhh Rats
Authors: Poudel Bibek , Fan Fan , Wang Shaoxun , Roman Richard J
Published: March 2022

The Fawn Hooded Hypertensive Rat (FHH) is a genetic model of hypertension, in which Add3 has been identified as a candidate gene for renal injury but the mechanism is unknown. The present study examined the effects of knockdown of Add3 on rat renal epithelial (NRK) cells which are the model system for podocytes and proximal tubular cells. Knockdown of the expression of Add3 using a 27-mer Dicer-substrate RNAi (DsiRNA) decreased cell viability using an MTS assay by 50% in comparison to cells treated with vehicle or scrambled DSiRNA (Add3DsiRNA, OD 0.5±0.1; untreated cells 0.9±0.1; NC-1 0.9±0.1; n=8, P<0.001). F-actin immunostaining revealed that Add3 DSiRNA markedly disrupted the cytoskeleton, and the F-actin staining intensity/cell ratio was significantly reduced (untreated 543±47, n=552 cells; NC-1 592±39, n=566 cells; Add3DsiRNA 430±58, n=385 cells, P<0.05). The maximum mitochondrial respiratory rate was reduced in Add3 DsiRNA treated cells (untreated 444±42; NC-1 414±32; Add3 DsiRNA 275±16 pmole/min/μg, P<0.01). Proton leak was higher (untreated 42±3; NC-1 40±4; Add3 DsiRNA 63±5 pmole/min/μg, P<0.002) and oxygen consumption coupled to ATP production was decreased in Add3 DsiRNA treated cells (untreated 229±12, n=9; NC-1 200±12, n=8; Add3 DsiRNA 146±11 pmole/min/μg, n=9, P<0.001). Spare respiratory capacity, an index of cell fitness, was reduced by knockdown of Add3 (untreated 154±42, n=9: NC-1 143±32, n=8; Add3DsiRNA 33±16 pmole/min/μg, n=9, P<0.001). Non-mitochondrial oxygen consumption rate (OCR/μg protein) increased in cells treated with Add3 DsiRNA (untreated 57±7; NC-1 80±11; Add3DsiRNA 116±15 pmole/min/μg, P<0.01) suggesting a possible metabolic switch to glycolytic oxygen consumption. In conclusion, knockdown of Add3 in NRK cells disrupts the actin cytoskeleton, promotes mitochondrial dysfunction and decreases cell viability. Loss of Add3 function may contribute to proteinuria in FHH rats by altering the cytoskeleton and promoting effacement and loss of podocytes and the reuptake of filtered protein in the proximal tubule.
Abstract P126: Regulation of Short Chain Fatty Acid Receptors in the Kidney by microRNAs is Influenced by Hydrogen Sulfide Supplementation
Authors: Weber Gregory , Pushpakumar Sathnur , Sen Utpal
Published: March 2022

Hypertension affects nearly one third of the adult US population and is a significant risk factor for chronic kidney disease (CKD). An expanding body of recent studies indicates that gut microbiome has crucial roles in regulating physiological processes through, among other mechanisms, one mode of short chain fatty acids (SCFA) and their target receptors. In addition, these SCFA receptors are potential targets of regulation by host miRNAs, however, the mechanisms through which this occurs is not clearly defined. Hydrogen sulfide (H
2
S) is an important gasotransmitter involved in multiple physiological processes and is known to alleviate adverse effects of hypertension such as reducing inflammation in the kidney. To determine the role of host microRNAs in regulating short chain fatty acid receptors in the kidney as well as the gut, C57BL/6J wild-type mice were treated with or without Ang-II (1000 ng/kg
-1
/min
-1
) and H
2
S donor GYY4137 (GYY) (133 μM/kg
-1
/d
-1
) for 4 weeks to assess whether GYY would normalize adverse effects observed in hypertensive mice and whether this was in part due to altered gut microbiome composition. We observed several changes of SCFA receptors and predicted microRNA regulators in the kidney among the different treatments. Haptoglobin, a marker for intestinal epithelial barrier integrity, was increased in hypertensive mice (97 ng/mL) compared to control (48 ng/mL), GYY (64 ng/mL) and Ang-II+GYY (71 ng/mL). The glomerular filtration rate (GFR) was improved in mice treated with Ang-II+GYY (963 μl/min
-1
/100 g body wt
-1
) compared with Ang-II (480 μl/min
-1
/100 g body wt
-1
) indicating improved kidney function. GYY supplemented mice had increased function (1219 μl/min
-1
/100 g body wt
-1
) compared to controls (981 μl/min
-1
/100 g body wt
-1
). The
Erysipelotrichia
class of bacteria, linked with altered SCFA production, was enriched in hypertensive animals but reduced with GYY supplementation. The TM7-3 phyla of bacteria are speculated to have anti-inflammatory properties and were found enriched in GYY only mice, supporting an anti-inflammation effect of H
2
S. These data point towards a role for miRNA regulation in hypertension and are beneficially influenced by H
2
S in both the kidney and potentially through changes in gut microflora.
Abstract P129: Antihypertensive Drugs and Risk of Cancer: A Systematic Review and Meta-Analysis of 391, 790 Patients
Authors: Che Roos Nur A , Alsanosi Safaa M , Alsieni Mohammed A , Gupta Mayetri , Padmanabhan Sandosh
Published: March 2022

Introduction:
The potential risk of cancer associated with antihypertensive drugs has been disputed for decades as additional outcomes from randomized controlled trials (RCTs), observational studies, and meta-analyses showed conflicting results.

Objective:
To assess the risk of cancer in patients exposed to major antihypertensive drug classes.

Methods:
We searched bibliographic databases for RCTs published between 1950 to December 2015 studying angiotensin-receptor blockers (ARB), angiotensin-converting enzyme inhibitors (ACEi), beta-blockers (BB), calcium channel blockers (CCB), and thiazide diuretics (TZ). RCTs with at least one year duration of planned active treatment and a minimum of 100 participants per treatment arm were eligible.

Main Outcome Measures:
Cancer and cancer-related deaths from the RCTs. Both fixed-effect and random-effects models were conducted and results were expressed as odds ratio (OR).

Results:
We identified 91 RCTs enrolling 391, 790 participants with an average follow-up of 3.4 years. There was no evidence of excess risk for cancer with ARB, ACEi, BB, and TZ (refer Fig.1). For CCBs, there was an increased risk of cancer (OR 1.07 95%CI 1.02, 1.1) with minimal heterogeneity (I
2
=13%). Subgroup analysis did not differ significantly between dihydropyridines (DHP) and non-dihiydropyridines subclasses. There was no statistically significant association between antihypertensive drug classes and risk of cancer deaths.

Conclusions:
Our results suggest that ARB, ACEi, BB, and TZ are not associated with increased risk of cancer. CCB therapy shows an increased risk of cancer. Further investigation on the risk of cancer with CCB is warranted.
Abstract P133: Angiotensin-(1-7) Does Not Acutely Lower Blood Pressure in Patients With Essential Hypertension
Authors: Arnold Amy C , Celedonio Jorge E , Paranjape Sachin Y , Biaggioni Italo , Gamboa Alfredo
Published: March 2022

Angiotensin (Ang)-(1-7) is a beneficial renin-angiotensin hormone that produces vasodilation to lower blood pressure (BP) in animal models of hypertension. There are limited clinical studies, however, and it is unclear if Ang-(1-7) contributes to BP regulation in human hypertension. We propose the difficulties in showing cardiovascular effects in previous clinical studies relates to the buffering capacity of the arterial baroreflex. In this study, we tested the hypothesis that Ang-(1-7) would produce negligible effects on BP with intact baroreceptors, and that the cardiovascular effects of this hormone would be unmasked following elimination of baroreflex buffering. To test this, we examined the effects of acute intravenous Ang-(1-7) infusion (ascending doses from 0.5 to 20 ng/kg/min) on supine BP in subjects with essential hypertension under intact conditions and following acute autonomic withdrawal with the ganglionic blocker trimethaphan in a randomized, open-label, crossover study. BP was restored to baseline levels following autonomic blockade with individually titrated phenylephrine doses. Seven subjects with essential hypertension completed this study (6 male; 48±4 years of age; 29±2 body mass index). All subjects were withdrawn from antihypertensive medications for at least two weeks, and were placed on a fixed sodium diet (150 mEq/day) for three days, prior to each study day. When comparing change from baseline to maximum dose, Ang-(1-7) did not alter systemic hemodynamics under intact conditions (systolic BP: 3±4 mmHg; diastolic BP: 3±1 mmHg; heart rate (0±1 bpm). In contrast to our hypothesis, Ang-(1-7) did not elicit a BP-lowering effect under autonomic blockade (systolic BP: 10±8 mmHg, p=0.299 vs. intact; diastolic BP: 7±3 mmHg, p=0.512; heart rate: -2±1 bpm, p=0.166). Plasma Ang-(1-7) was measured in 4 subjects and showed an approximate 3-fold increase with infusions [0.8±0.7 baseline vs. 2.1±1.2 ng/mL after Ang-(1-7)]. These findings suggest that infusion of Ang-(1-7) to levels within a physiologic range does not acutely induce vasodilation to lower blood pressure in essential hypertension. We cannot exclude that Ang-(1-7) lowers BP by sympathetic inhibition, since those pathways were excluded by our study design.
Abstract P139: Dual Angiotensin Receptor and Neprilysin Inhibition Improves Renal Hemodynamics and Reduces Kidney Damage in Diabetic Rats
Authors: Uijl Estrellita , Clahsen-van Groningen Marian C , Joles Jaap A , Hoorn Ewout J , Danser Alexander H
Published: March 2022

Dual blockade with an Angiotensin Receptor/Neprilysin Inhibitor (ARNI) reduces proteinuria and glomerulosclerosis in diabetic TGR(mREN2)27 rats (i.e., rats displaying angiotensin II-dependent hypertension) more strongly than single AR blockade (ARB), despite a similar effect on blood pressure. Here we investigated whether this is due to improved renal hemodynamics and/or suppression of renal inflammation. TGR(mREN2)27 rats were made diabetic with streptozotocin for 12 weeks, and treated with placebo (n=10), valsartan (ARB; n=8) or valsartan/sacubitril (ARNI; n=8) from week 9-12. Blood pressure was measured by telemetry. Effective renal plasma flow (eRPF) and glomerular filtration rate (GFR) were assessed by quantifying para-aminohippuric acid and inulin clearances. Renal inflammation was quantified by qPCR (CD68 and CD3ε expression, representative for macrophages and T cells, respectively) and fluorescent activated cell sorting (FACS) analysis. ARNI and ARB lowered blood pressure identically, while only ARNI reduced albuminuria. Severe, chronic ischemia and globally sclerotic glomeruli occurred less frequently in kidneys of ARNI-treated animals vs. ARB-treated animals and controls. ARNI, but not ARB, increased eRPF, and a similar trend was observed for GFR. No treatment affected filtration fraction. ARNI decreased CD68 mRNA expression in both renal cortex and medulla, while ARB increased CD68 as well as CD3ε expression in renal medulla. FACS analysis revealed no differences between the treatment groups in the immune-cell fractions that had infiltrated the kidney. In conclusion, improved renal hemodynamics, combined with reduced macrophage infiltration, may underlie the stronger beneficial effects of ARNI on albuminuria and renal histology in diabetic TGR(mREN2)27 rats versus ARB.
Abstract P140: Serum Chloride Predicts Mortality Risk in Type 2 Diabetes - Analysis of 91,159 Patients From the West of Scotland
Authors: McCallum Linsay , Sainsbury Christopher A , Jones Gregory C , Padmanabhan Sandosh
Published: March 2022

Objective:
Low serum chloride (Cl
-
) is associated with increased risk of death in those with heart failure, hypertension or chronic kidney disease. We sought to investigate the association of serum Cl
-
with risk of cause-specific death in adults with type 2 diabetes mellitus (T2DM).

Methods:
Data was available for 91,159 adults from the West of Scotland with T2DM from NHS Greater Glasgow and Clyde Safe Haven with 10 years follow up. Two groups were created: serum Cl
-
<100 and Cl
-
≥100 mmol/L. Cox-PH models, adjusted for age, sex and serum sodium (Na
+
), were used to assess the association between serum Cl
-
and risk of death (all-cause mortality, vascular death, death from myocardial infarction (MI), death from heart failure, death from stroke, death from cancer).

Results:
There were 13,459 patients with serum Cl
-
<100 mmol/L; 53% were male with median age 62.5 (IQR 50.9-73.1) years and median Na+ 136 (133-138) mmol/L. There were 77,757 patients with serum Cl
-
≥100 mmol/L; 53% were male with median age 61.2 (IQR 50.2-71.4) years and median Na
+
139 (IQR 138-141) mmol/L. Serum Cl
-
<100 mmol/L was associated with an 44% increased risk of all-cause mortality (N=20,304, HR 1.44[95% CI 1.38-1.49]; p <0.0001), independent of serum Na
+
(Figure). The increased mortality risk of serum Cl
-
<100 mmol/L was observed for cardiovascular mortality (N=6,323, 1.41[1.31-1.51]; p <0.0001); death from MI (N=1,986, 1.42[1.25-1.60]; p <0.0001); stroke (N=1,590, 1.24[1.08-1.42]; p 0.003); heart failure (N=200, 1.38[0.95-2.0]; p 0.09) and cancer (N=5,577, 1.12[1.04-1.21]; p 0.003).

Conclusions:
Serum chloride <100 mmol/L was associated with increased risk of death in adults with type 2 diabetes mellitus.
Abstract P141: Fetuin B, a Hepatokine, Causes Acute Endothelium-dependent Vascular Relaxation and Decrease Blood Pressure
Authors: Martins França Lucas O , Zhang Youhua , de Andrade Paes Antonio Marcus , Carrillo-Sepulveda Maria Alicia
Published: March 2022

Non-alcoholic fatty liver disease (NAFLD) has been implicated in the pathogenesis of type 2 diabetes (T2DM) and is a direct risk factor to the development of cardiovascular diseases. Fetuin B was identified as a hepatokine secreted by steatotic hepatocytes and released in large amount in T2DM patients. While previous reports showed that fetuin A negatively regulates endothelial function, studies related to fetuin B and vascular function remain undetermined. Thus, we tested the hypothesis that fetuin B impairs endothelial function and arterial blood pressure. Using an invasive left ventricular (LV) catheterization via the carotid artery, we found that
in vivo
acute administration of recombinant human fetuin B (0.5μg/g body weight) dropped systolic blood pressure in mice within 30 minutes ( 110 ± 2 vs 94 ± 2mmHg, p<0.05). Next, we tested whether fetuin B alters endothelial-dependent relaxation. Aortic rings were incubated acutely with fetuin B (50ng/mL) for 30 minutes prior to functional vascular studies using a wire myograph. Fetuin B potentiated acetylcholine-induced endothelial-dependent relaxation (95.2 ± 2 vs 85.0 ± 3 %, p<0.05, n=3). Fetuin B did not significantly affect vascular contraction induced by phenylephrine. Cultured human umbilical vein endothelial cells stimulated with Fetuin B for 12 hours displayed augmented phosphorylation of eNOS in the serine 1177 (2.5-fold of increase vs unstimulated cells, p<0.05). Our data showed that our hypothesis was contested since fetuin B facilitated vasorelaxation dependent of endothelium and acutely decreased blood pressure. Together the findings of this present study suggest that increased levels of fetuin B acutely play a protective endothelial vascular role. We are currently testing the long-term effects of fetuin B on the vasculature of T2DM animal models.
Abstract P143: Pulsatile Stress in the Hypertensive Elderly versus Young Patients
Authors: Shofu Abimbola , Saung May , Awan G. Mustafa , Omar Bassam , Malozzi Christopher
Published: March 2022

Background:
Hypertensive patients suffer wide pulse pressure (PP) with age, an independent marker of cardiac events. Changes in the heart rate (HR) may decrease pulsatile stress (PPxHR).

Objectives:
To examine pulsatile stress in hypertensive elderly patients, as a potential compensatory mechanism to widened pulse pressure.

Methods:
Clinic charts were reviewed with hypertension as a diagnosis; 200 encounters were reviewed and divided into 2 groups; group 1 (young) were patients < 60 years of age (n=116), and group 2 (elderly) were patient ≥ 60 years of age (n=84). The difference between the groups with regards systolic blood pressure (SBP), diastolic blood pressure (DBP), pulse pressure (PP), heart rate (HR), and pulsatile stress (PPxHR) were analyzed using Student’s t-Test.

Results:
The mean age of patients was 68±9 years in elderly versus (VS) 49±9 years in the young. SBP was marginally higher in the elderly at 134±20 vs 128±18 mmHg in the young; P = 0.04. DBP and HR were significantly lower in the elderly vs the young at 80±13 vs 86±13 mmHg, and 67±11 vs 76±14 BPM respectively; P < 0.01. PP was significantly higher in the elderly at 55±18 vs 42±13 mmHg in the young; P < 0.01. Pulsatile stress (PPxHR), however, was not significantly different in the elderly at 3,795±1,506 vs 3,477±1,246 in the young; P = 0.11.

Discussion:
Elderly patients suffer elevated pulse pressure, an independent predictor of cardiac risk. In our cohort, the pulse pressure was significantly higher, as expected, in elderly patients. However, the heart rate in elderly patients was significantly lower, therefore causing no significant difference in the pulse pressure-heart rate product (a measure of pulsatile stress) compared with younger patients. Overall, the medical management in our cohort was guideline-based and was not significantly different among the two groups. Whether the slower heart rate seen in elderly patients is compensatory, or merely a manifestation of intrinsic sinus node disease is unclear. Further studies to compare the response of pulsatile stress to exercise in elderly versus younger patients may help clarify this issue.
Abstract P151: Salt Sensitivity in Male and Female C57BL/6J Mice: Role of Renal Angiotensin and Dopamine Receptors and Sodium Transporters
Authors: Ma Xiaobo , Zhou Donghai , Diao Zhenyu , Asico Laureano D. , Escano Crisanto S. , Cuevas Santiago , Armando Ines , Jose Pedro A. , Wang Xiaoyan
Published: March 2022

To test if there is a sex difference in the salt sensitivity of C57Bl/6J mice, we studied blood pressure (BP), renal dopamine receptors, and sodium transporters in response to high salt diet (4% NaCl, 1 wk) and candesartan. Similar to males, the night-time systolic BP (SBP, telemetry, n=4) in females started to increase on day 1, peaked on day 2 (130±1 vs 117±1, mm Hg) and remained at high levels (126±1); the daytime SBP started to increase on day 2 that became significant on day 6 (124±1 vs 111±1). The high salt-diet induced-increase in SBP was prevented by candesartan (1 mg/kg, 1 wk, subcutaneously via osmotic mini-pump) (82±3 vs. 117±2 in males; 86±2 vs. 121±1 in females, under anesthesia, n=5/group). There were no sex differences in the SBP response to diet and candesartan, food and water intakes, urinary excretions of water and electrolytes, and serum concentrations of creatinine and electrolytes on high and normal salt diet. In females fed a high salt diet, candesartan increased renal D
1
R (151±12, immunoblotting, % of control, n=5/group) and D
5
R (156±5) but not D
2
R, D
3
R
,
or D
4
R protein expression, increased renal mRNA expression of D
1
R(160±17) but not D
5
R (real-time PCR), and decreased the renal protein expressions of sodium-hydrogen exchanger isoform 3 (36±6), sodium-potassium-2 chloride cotransporter (8±2), sodium-chloride cotransporter (30±3), and α (55±4), β (60±8) and γ (9±1) epithelial sodium channel, but not type 2 sodium phosphate cotransporter and α1Na
+
K
+
ATPase. Those changes were also seen in males except that renal D
1
R protein expression was not increased. Under normal salt intake, AT
1A
R KO females (C57Bl/6J background) had increased renal protein expressions of D
1
R (152±8), D
5
R (131±6), and D
4
R (114±4), but not D
2
R and D
3
R; renal protein expressions of sodium-hydrogen exchanger isoform 3 (47±8), sodium-potassium-2 chloride cotransporter (52±11), and α (42±9) and γ (46±7) epithelial sodium channel were decreased. We conclude that the increase in BP caused by high salt diet and the effect of AT
1
R blockade on BP, renal dopamine receptors and sodium transporters are similar in male and female C57Bl/6J mice . The consequences of the sex-related differential regulation of D
1
R and D
5
R, in pathophysiology, other than BP, remain to be determined.
Abstract P152: Female Mice Are Not Protected From High Fat Diet-induced Metabolic Dysfunction
Authors: Friemel Taylor , Loloi Justin , Bingaman Sarah S , Arnold Amy C
Published: March 2022

Female clinical populations are generally protected from obesity-related blood pressure and metabolic complications such as hypertension and type II diabetes, despite increased adiposity compared to males. Similar cardiovascular protection has been observed in obese female mice produced by high fat diet (HFD) feeding, a well-established animal model of obesity. The impact of HFD on glucose homeostasis and insulin action in relation to gender differences, however, remains unclear. In this study, we tested the hypothesis that female mice would be protected from HFD-induced glucose intolerance and insulin resistance. To test this, five-week old male and female C57BL/6J mice were placed on control chow diet or 60% HFD for 12 weeks (n=11 chow male; n=6 chow female; n=15 HFD male; n=5 HFD female). Body composition was measured and glucose tolerance testing (GTT; 2g/kg of 50% dextrose) and insulin tolerance testing (ITT; 0.75 units/kg) were performed during the last week of diet. Females had lower body mass compared with males over the 12-week study period. Both genders increased body mass to a similar extent in response to chow diet (24.6±1.7 male vs. 26.5±2.3% female; p=0.517), and HFD (85.0±2.1 males vs. 79.8±6.7% females; p=0.332). HFD females had similar adiposity compared with males (22.9±0.7 males vs. 22.5±1.6% females; p=0.780). HFD reduced insulin sensitivity in male mice [area under the curve (AUC) for blood glucose levels during ITT: -5903±662 chow vs. -1748±1024 HFD; p=0.005] and female mice (-6599±966 chow vs. -2904±1507 HFD; p=0.041), with no differences between genders (p=0.567). HFD also resulted in glucose intolerance in male (AUC for blood glucose levels during GTT: 40262±1769 chow vs. 52800±2502 HFD; p=0.001) and female (36951±2270 chow vs. 55507±3582 HFD; p=0.001) mice, with no gender differences (p=0.582). These data suggest that in contrast to our hypothesis, HFD female mice develop obesity-related insulin resistance and glucose intolerance to a similar extent as males. These findings have important implications for use of this mouse model to study impact of gender on metabolic function in obesity.
Abstract P155: Renal Responses to Experimental Angiotensin II Induced Hypertension (Ang-HTN) in Female Rats
Authors: Veiras Luciana C , Prescott Jessica , Ralph Donna , McDonough Alicia
Published: March 2022

Compared to males, female Sprague Dawley rats (SDR) at baseline exhibit lower abundance of Na
+
/H
+
exchanger (NHE3), Na
+
-Pi transporter (NaPi-IIa), paracellular claudin-2 (Cld2), and higher NHE3p (an inactivation marker) as well as lower fractional reabsorption along the proximal tubule (PT); along the distal tubule-collecting duct (DT-CD) females exhibit greater Na-Cl cotransporter (NCC) abundance and activating phosphorylation (NCCp), as well as greater epithelial Na
+
channel (ENaC) subunits’ abundance and activating cleavage. In male SDR, AngII-HTN (400 ng/kg/min, 14 days) increases DT-CD NCC, NCCp and ENaC abundance and activating cleavage, while PT NHE3 and NaPi-IIa are decreased or unchanged, accompanied by a natriuresis and diuresis. This study aimed to determine the effect of AngII-HTN in female SDR using the same protocol applied to males. AngII-HTN: increased BP (tail cuff) from 111 ± 3 to 193 ± 8 mmHg (equivalent to males), increased UV 1.7-fold (vs. 3 fold in males) and decreased UOsm 40% (equivalent to males). AngII-HTN increased: cortical thick ascending limb Na
+
-K
+
- 2Cl
-
cotransporter (TAL NKCC2) and NKCC2p in females by 2.2 and 1.8-fold (p<0.002), did not change NCC or NCCp abundance, increased ENaC subunits: α by 1.7-fold, cleaved α by 2.4-fold, β by 1.4-fold, cleaved γ by 1.3-fold (all p< 0.01). In the PT of females, AngII-HTN increased NHE3p by 1.4-fold, NaPi2 by 1.2-fold and Cld2 by 2.2-fold (all p<0.005). In conclusion, despite similar hypertensive and diuretic responses to AngII-HTN in females as males, a distinct pattern of sodium transporters’ regulation along the nephron during AngII-HTN is observed in females: 1) abundance of TAL NKCC2, NKCC2p, not increased in males, is increased in females while DCT NCC and NCCp, stimulated in males and higher at baseline in females, is not increased in females, 2) CD ENaCs are similarly stimulated in both sexes, and 3) PT NHE3p, higher at baseline in females, is further increased by AngII consistent with NHE3 inactivation that could contribute to pressure diuresis.

Supported by NIH NIDDK DK083785 and AHA Grant in Aid Western States Affiliate 15GRNT23160003
Abstract P158: MicroRNA Profiling in Peripheral Blood Mononuclear Cells From Hypertensive Patients With or Without Chronic Kidney Disease
Authors: Huo Ku-Geng , Fraulob-Aquino Julio C , Richer Chantal , Rehman Asia , Briet Marie , Boutouyrie Pierre , Lipman Mark , Sinnett Daniel , Paradis Pierre , Schiffrin Ernesto L.
Published: March 2022

Background:
Hypertension (HTN) and chronic kidney disease (CKD) are global health disorders that are epidemiologically associated. The immune system has been shown to play a role in HTN and CKD in animal models. Activation of T cells has been observed in peripheral blood mononuclear cells (PBMCs) of patients with HTN. MicroRNAs (miRNAs) are crucial post-transcriptional regulators of immune cells. Whether miRNAs play a role in the activation of immune cells in HTN and CKD in humans remains unknown. We aimed to address this question by identifying differentially expressed (DE) miRNAs and their mRNA targets in PBMCs of HTN and CKD patients.

Methods and Results:
Normotensive, HTN (systolic blood pressure (BP) >135 mm Hg or diastolic BP of 85-115 mm Hg with BpTRU) and CKD subjects (estimated glomerular filtration rate <60mL/min/m
2
) (n=15-16) were studied. PBMCs were isolated from 30 ml of whole blood and used for total RNA extraction with the mirVana miRNA isolation kit. cDNA libraries were prepared using the TruSeq small RNA prep kit and the TruSeq stranded total RNA prep kit, and were sequenced by Illumina HiSeq 2500. DE miRNAs (
P
<0.05) were identified using EdgeR, which found 41 up- and 38 down-regulated miRNAs, as well as 101 up- and 316 down-regulated mRNAs uniquely associated with the hypertensive group, while 11 up- and 18 down-regulated miRNAs, as well as 153 up- and 73 down-regulated mRNAs were found uniquely associated with the CKD group. Meanwhile, 4 up- and 8 down-regulated miRNAs, as well as 13 up- and 19 down-regulated mRNAs were found in both groups. Target Scan was used to predict DE miRNA targets in the DE mRNAs. Enrichment analysis showed that the HTN-associated DE miRNA-targeting DE genes were highly enriched in gene ontology (GO) terms involved in cytosolic transport, protein kinase B (PKB) signalling and RNA 3’ processing (
q
<0.001), while the CKD-associated DE miRNA-targeting DE genes were highly enriched in GO terms involved in immune response, ribosomal process and metal ion homeostasis (
q
<0.001).

Conclusions:
DE miRNAs were identified in PBMCs of HTN and CKD patients. Enrichment analysis in DE miRNA-targeting DE mRNAs revealed GO terms that could be linked to different degrees of immune cell activation in HTN and CKD.
Abstract P170: Hypertensive Pattern After Kidney Transplantation
Authors: Tantisattamo Ekamol , Vutthikraivit Possawat , Mopuru Haritha
Published: March 2022

Background:
The patterns and factors contributing to post-transplant hypertension are unknown.

Methods:
Seventy kidney transplant recipients enrolled during a 10-month period were divided into deceased donor renal transplant (DDRT) or living donor renal transplant (LDRT) groups. Risk of development for HTN (SBP ≥140 or DBP ≥90 mmHg) between these 2 groups were compared.

Results:
There was 50 patients (71.4%) in a DDRT group. Mean age±SEM of the DDRT and LRRT were 52.8±1.7 and 52.3±2.7 years, respectively (p=0.872). Mean pre-transplant SBP and DBP were not significantly different between both groups. DDRT group was at greater risk to develop post-transplant systolic HTN than the LRRT group but not statistically significant (HR 1.145, CI 0.616 - 2.130, p=0.668; Figure 1). However, the risk to develop diastolic HTN was significantly lower in DDRT than LRRT groups (HR 0.506, CI 0.265 - 0.965, p=0.039). The risk of developing post-transplant diastolic HTN were not modified by age (<65 and ≥65 years old; HR of interaction 0.246, CI 0.025 - 0.450, p=0.232). After controlling for several factors including age, the risk for developing diastolic HTN was 0.422 times lower in DRRT than that of LRRT group (CI 0.187 - 0.956, p=0.039; Figure 2).

Conclusion:
DRT recipients are at higher risk of developing systolic HTN but lower risk for diastolic HTN in DDRT recipients. This pattern of post-transplant HTN is similar to non-transplant elderly patients, whose pulse pressures are widened. Since there was no difference in mean age between DDRT and LRRT groups, underlying process apart from age may affect post-transplant HTN in DDRT and subsequently poorer renal allograft survival in DDRT than that of LRRT.
Abstract P179: Pulmonary Spinal Sympathetic Afferent Activation in Post-myocardial Infarction Rats
Authors: Shanks Julia , Xia Zhiqiu , Rozanski George J , Schultz Harold D , Lisco Steven J , Zucker Irving H , Wang Han-Jun
Published: March 2022

Recently, we reported activation of pulmonary spinal afferents by topical application of bradykinin (BK) to lung surfaces evokes a potent sympatho-excitatory reflex, including increased blood pressure (BP), heart rate (HR) and renal sympathetic nerve activity (RSNA) in urethane-α-chloralose anesthetized vagotomized rats. This finding suggests a new previously undocumented pulmonary sympathetic afferent reflex (PSAR). Preliminary data was reported in abstract form at the Association of University Anesthesiologists 64
th
Annual meeting. Expanding this work, we examined the activation of the PSAR at different time points post myocardial infarction (1 month vs. 5 months post MI) and at different degrees of infarct size (15%-35% (moderate) vs. above 35% (large) of left ventricle). Following
bilateral vagotomy
, we applied filter paper (3 х 3 mm) saturated with BK (10 μg/ml) to the ventral lung surface to stimulate the PSAR in both urethane- α-chloralose anesthetized sham-operated and MI rats. Application of BK to the lungs resulted in increased BP, HR and RSNA in all sham and MI rats. Compared to sham rats, the BK-induced sympatho-excitatory response was significantly increased in 1-month moderate and 1-month large MI rats as well as in 5-month moderate MI rats. The BK-induced sympatho-excitatory response was significantly blunted in 5-month large MI rats (Table 1). These data suggest that the activation of pulmonary spinal afferents in the post-MI state may be an independent risk factor for sympatho-excitation. Further studies are needed to understand the differential effects of pulmonary spinal afferent activation at the transition from the post MI state to heart failure.
Abstract P180: Blood Pressure Lowering During Chronic Baroreflex Activation: Don’t Forget the Heart
Authors: Clemmer John S , Lohmeier Thomas E , Iliescu Radu , Pruett W. A , Hester Robert L
Published: March 2022

Electrical stimulation of the baroreflex chronically suppresses sympathetic activity and arterial pressure (AP) and is currently being evaluated for the treatment of resistant hypertension. The antihypertensive effects of baroreflex activation (BA) are often attributed to renal sympathoinhibition. However, BA also decreases heart rate (HR) and, surprisingly, robust blood pressure lowering occurs even after renal denervation. Accordingly, responses to BA were simulated under normal conditions and after blockade of changes in renal sympathetic nerve activity (fixed RSNA) and autonomic activity to the heart (fixed HR) using an established mathematical model of human physiology (HumMod). Three week responses to BA closely mimicked our actual experimental observations in dogs including a 40% decrease in plasma [norepinephrine] (and RSNA in the simulation). With RSNA and HR fixed at control levels, mean AP (MAP), HR, right atrial pressure (RAP) and plasma atrial natriuretic peptide (ANP) responses to BA were:

Changes in autonomic activity to the heart during BA lead to bradycardia, increases in atrial pressure and ANP secretion. Increased ANP and suppression of RSNA enhance renal excretory function and normally account for most of the hypotensive response to BA. However, when suppression of RSNA is not possible, blood pressure lowering in response to BA is not appreciably impaired due to inordinate fluid accumulation and further increases in atrial pressure and ANP secretion. These simulations provide a mechanistic understanding of experimental and clinical observations showing that BA effectively lowers blood pressure in subjects with previous renal denervation.
Abstract P184: Muscarinic Receptor Modulators’ Effect on Cilia Structure and Nitric Oxide Release
Authors: AbouAlaiwi Wissam A , Gibson Hayley
Published: March 2022

Primary endothelial cilia are microtubule-based organelles that act as mechano-sensors to help detect, and respond to changes in the extracellular environment. One of these responses includes its ability to detect fluid shear stress and translating that signal into a biochemical process to synthesize nitric oxide, an endogenous vasodilator. Abnormal cilia structure and function has been known to cause a myriad of human disorders, including polycystic kidney disease and hypertension. It is also well documented that muscarinic acetylcholine receptors subtype M1 also plays a key role in producing a vasodilation response in the vasculature. However, nothing is known about the relationship between primary endothelial cilia and the M1 receptor. To further explore the relationship between AChM1R and the mechanosensory function of primary cilia, the effects of muscarinic modulators on cilia length and function in wild-type, and mechano-insensitive cilia mutant endothelial cells,
Pkd1
–

/

–
(dysfunctional cilia) and

Tg737
orpk/orpk

(cilia-less) were examined. We show that AChM1R localizes to primary endothelial cilia. AChM1R activation lead to the significant increase cilia length in endothelial cells treated with CDD102A, an AChM1R agonist (1.21 ± 0.07 vs. 2.33 ± 0.04 for wild-type, 1.02 ± 0.01 vs. 1.44 ± 0.01 for
Pkd1
–

/

–
, and 0.024 ± 0.005 vs. 0.3 ± 0.004 for

Tg737
orpk/orpk

) compared to non-treated cells. Treating endothelial cells with pirenzepine, an AChM1R antagonist, led to a significant decrease of cilia length (1.34 ± 0.02 vs. 1.15 ± 0.01 in wild-type, and 1.16 ± 0.01 vs. 0.71 ± 0.01 in
Pkd1
–

/

–
) compared to non-treated cells. Treatment with CDD102A also significantly upregulated the expression of AChM1R, and phosphorylated eNOS. Our data clearly suggested that modulating cilia sensory function could have a positive influence on nitric oxide generation and blood pressure regulation.
Abstract P185: Prognostic Value of Endothelial Markers in Hypertensive Nondiabetic Patients
Authors: Murashko Natalia , Bragina Anna , Bragina Galina , Podzolkov Valery
Published: March 2022

Aim:
to study the prognostic value of the serum levels of stable nitric oxide metabolites (NOx), endothelin-1 (E1), homocystein (HC), von Willebrand factor (Wf), tissue plasminogen activator (tPA), in hypertensive nondiabetic patients without cardiovascular disease.

Methods:
124 patients with hypertension (HTN), without diabetes were enrolled, the mean age was 51.4±6.5y, the mean duration of HTN was 8.5±7.6 y, 36 % were males, 35% were smokers, 54% were obese. The cardiovascular risk was estimated according to the SCORE (Systematic Coronary Risk Evaluation) system. Plasma NOx levels were determined by spectrophotometry, E1, HC, Wf, tPA levels by enzyme immunoassay. The follow-up period was 8±1.1y. Statistical analysis was done using the SPSS 11.1 software.

Results:
On initial investigation all patients were stratified according to the SCORE risk levels. The increase of SCORE risk levels were associated with the elevation of serum NOx, E1, HC, and Wf concentrations. The mean plasma NOx concentration increased along with the SCORE risk level: it was 36.4±12.7 in low risk, 41.1±15.7 in moderate risk, 44.9±19.8 in high risk, and 50.4±19.1 umol/L in very high risk categories (<0.05 between the low and high risk groups). The tPA levels did not differed in relation to the SCORE risk estimates. The SCORE risk level correlated with serum concentrations of NOx (r=0.74, p=0.0001), HC (r=0.54, p=0.0001), and Wf (r=0.43, p=0.001).

Conclusions:
The stable nitric oxide metabolites, homocystein, and von Willebrand factor are the markers of oxidative/nitrosative stress severity. Our results are indicative that this substances may be of prognostic value in hypertensive nondiabetic patients.
Abstract P194: High Intensity Interval Training Protects the Heart
Authors: Jeremic Nevena , Theilen Nicholas T , Weber Gregory J , Zivkovic Vladimir , Srejovic Ivan , Jakovljevic Vladimir , Tyagi Suresh C
Published: March 2022

Background:
Human studies have shown high intensity interval training (HIIT) can have beneficial effects on the heart. The main goal of this study is to show 15 minutes of exercise with high intensity can has the same protective effects on the cardiovascular system as endurance training (ET) in healthy and diseased animals.

Methods:
For this study we used mouse (C57BL/6J) and rat (Wistar albino) models. We had three group of mice and rats: sedentary-control (CTRL), ET, and HIIT groups. First, 10-12 week old mice were treated with either ET or HIIT for 4 weeks. We performed heart ultrasonography, cardiomyocyte contractility, blood flow of the abdominal aorta and Western blot analysis for SOD-1, SOD-2, and citrate synthase to test cardiovascular differences between groups. Further, we used DHE staining, ATP production assay and O
2
-
consumption kits. Second, 10-12 week old rats were treated with either ET of HIIT prior to ischemia/reperfusion injury on a Langendorff apparatus. Cardiodynamic data on dp/dt max, dp/dt min, SLVP, DLVP, heart rate, coronary flow and blood pressure were collected to observe differences between groups.

Results:
Our data reviled an increase in blood flow of mice abdominal aorta in both exercise groups compared to control but not between exercise groups itself (BF CTRL: 2218.7±10.0; BF ET: 2481.9±10.5; BF HIIT:2450.6±12.1). Ejection fraction was increased in HIIT compared to other groups (EF CTRL: 76.58±1.8; EF ET: 74.5±2.0 and EF HIIT: 84.83±2.4); Fractional shortening was increased in HIIT group compared to other groups (FS CTRL: 44.49±0.9; FS ET: 42.79±1.08; FS HIIT: 52.51±1.9). LIVDs was decreased in HIIT group compared to endurance, while in endurance was increased compare to control group (LIVDs CTRL: 1.11±0.3; LIVDs ET: 2.33±0.2; LIVDs HIIT: 1.4±0.2). DHE staining for ROS revealed no differences among groups.

Conclusion:
These findings indicate that HIIT have specific protective effects on the cardiovascular system compared to endurance training, even with possible higher heart contractility. People often cite the time as an excuse for lack of physical activity, however time is no longer an excuse.
Abstract P207: Zeta Potential of Erythrocyte Membranes and Hypertension Characteristics in Patients With Metabolic Syndrome
Authors: Sapacheva Mariya G , Pisarev Mikhail V , Koroleva Tatyana V , Podzolkov Valery I
Published: March 2022

Aim:
to study the relationship between total zeta potential of erythrocyte membranes (TZPEM) and duration, grade, and target organ damage/associated clinical conditions of hypertension in patients with metabolic syndrome (MS).

Material and Methods:
90 patients with metabolic syndrome (38 men and 62 women with mean age of 61.4±7.2 years and average hypertension duration of 7.19±5.4 years) were studied. Metabolic syndrome, hypertension grade and target organ damage were diagnosed according to the 2013 ESC Guidelines. The plasma TZPEM levels were detected by the Alcian cationic dye adsorption on the erythrocyte membrane.

Results:
to assess the relationship between hypertension characteristics and TZPEM the patients with MS were divided into groups according to the grade of hypertension, target organ damage/associated conditions and hypertension duration (below 5, 5-10, and more than 10 years). Hypertension was registered in all the patients in the main group. There were no significant differences in TZPEM between patient groups with various hypertension grades (1.63±0.03×10
7
in 1 grade hypertension, 1.58±0.05×10
7
in 2 grade hypertension, and 1.60±0.04×10
7
in 3 grade hypertension, p>0.05). Meanwhile, we found a significant reduction in TZPEM related to the target organ damage/associated conditions (1.63±0.03 ×10
7
, 1.60±0.04×10
7
i 1.54±0.04×10
7
in no target organ damage/target organ damage/associated clinical conditions, respectively, p<0.05). Also a significant reduction in TZPEM in association with the hypertension duration was revealed. The mean TZPEM was 1.65±0.04 ×10
7
, 1.61±0.03×10
7
, and 1.56±0.05×10
7
in patients with less than 5 years, 5-10 years, and more than 10 years duration of hypertension, respectively (p<0.05). A significant negative correlation between TZPEM and duration of hypertension was found in patients with MS (r=-0.56, p< 0.05).

Conclusion:
hypertension grade in patients with MS poorly correlates with TZPEM, whereas TZPEM was significantly lower with increasing duration of hypertension. TZPEM was also significantly lower in patients with target organ damage and/or associated clinical conditions which implies prognostic significance of TZPEM in patients with metabolic syndrome.
Abstract P232: Superoxide Increases Renin Activity, Renal Angiotensin II Type 1 Receptor (at1r) Function and Blood Pressure in Rats
Authors: Wang Xitao , Asghar Mohammad , Saleem Mohammad
Published: March 2022

We examined role and mechanism of superoxide in renal AT1R function contributing to hypertension in Sprague-Dawley rats. Rats were divided into 4 groups and treated with 1. vehicle, 2. superoxide dismutase (SOD) inhibitor diethylthiocarbamate (DETC, 10mg/kg, i.p./daily for 2 weeks), 3. DETC+tempol (an SOD mimetic, 2 mM in drinking water), and 4. tempol only. Rats were sacrificed, blood plasma and kidneys obtained for biochemical studies. Superoxide [Fluorescence Unit (FU): control vs DETC vs DETC+tempol vs tempol, 0.10±0.006 vs 0.13±0.01 vs 0.09±0.007 vs 0.09±0.004] but not hydrogen peroxide levels increased in the renal tissues of DETC-rats than in vehicle-rats, which decreased in DETC+tempol rats. Nuclear levels of acetylated-Sp3 transcription factor, an index of its activity, (Density Unit: control vs DETC vs DETC+tempol vs tempol, 0.10±0.01 vs 0.17±0.02 vs 0.10±0.01 vs 0.13±0.02) and membranous AT1R proteins levels (Density Unit: control vs DETC vs DETC+tempol vs tempol, 0.98±0.32 vs 2.93±0.40 vs 0.99±0.24 vs 0.77±0.23) increased in DETC-rats, which were attenuated in DETC-tempol-rats. Moreover, plasma renin activity (FU: control vs DETC vs DETC+tempol vs tempol: 0.13±0.006 vs 0.19±0.04 vs 0.12±0.005 vs 0.13±0.01) increased in DETC-rats, which decreased in DETC+tempol-rats. Second set of rats underwent the same treatment as above, anesthetized, blood pressure (BP) and renal AT1R function (in terms of natriuresis) in response to AT1R blocker
candesartan
(10μg/kg, i.v. bolus) were determined. Systolic BP increased in DETC-rats than in vehicle-rats, which decreased in DETC+tempol-rats (mmHg: control vs DETC vs DETC+tempol vs tempol: 118.6±2.72 vs 136.7±2.96 vs 118.1±3.81 vs 123.1±6.88). Natriuresis in response to candesartan (cande) increased in vehicle-rats, which further increased in DETC-rats while decreased in DETC+tempol-rats (μmols/min: control vs control+cande vs DETC vs DETC+cande vs DETC+tempol vs DETC+tempol+cande vs tempol vs tempol+cande, 0.32±0.07 vs 0.58±0.10 vs 0.19±0.05 vs 1.06±0.34 vs 0.23±0.05 vs 0.49±0.14 vs 0.27±0.04 vs 0.66±0.11). Taken together, our results suggest that superoxide via Sp3 activation increases renin activity, membranous AT1R levels and function contributing to hypertension in rats.