bluuebunny/crossref_metadata_2025_split huggingface dataset:
PS-BPB07-4: LONG-TERM PATHOLOGICAL CHANGES IN ABLATED RENAL NERVES FOLLOWING CATHETER-BASED RADIOFREQUENCY RENAL DENERVATION IN A NORMOTENSIVE SWINE MODEL
Authors: Schlaich Markus , Tunev Stefan , Sharp Andrew , Lee David P , Finn Aloke , Trudel Julie , Kandzari David E 
Published: January 2023

Objective:
Randomized, sham-controlled clinical trials with catheter-based radiofrequency (RF) renal denervation (RDN) have demonstrated safety and efficacy of the procedure through 3 years. However, pre-clinical reports of functional renal nerve regrowth are inconsistent. In this analysis in normotensive swine, we assessed the specificity of RF ablation around the renal arteries out to 28 days and quantified the long-term pathophysiological outcomes through 180 days.

Design and method:
RF ablations were delivered to the renal arteries of normotensive swine using the Symplicity SpyralTM catheter (Medtronic, Santa Rosa, CA, USA). For the tissue specificity analysis, RF RDN was performed in 14 swine, and serial sections of the renal artery were harvested from 6 pigs at day 7, and 8 pigs at day 28. Surrounding anatomic tissues of the treated areas (including ureter, kidney, lymph nodes, skeletal muscle, adrenal glands, and renal nerves) were evaluated in response to RDN using a semi-quantitative scoring system (Figure). To assess durability, RF RDN was performed in a separate group of 14 normotensive swine, with an additional 14 pigs serving as control. Serial sections of renal artery were harvested at day 7 (n = 6 animals per group) and day 180 (n = 8 per group) post-procedure. In addition, matrixed samples from renal cortex were collected for each pig in both studies and subjected to bioanalytical quantification of cortical norepinephrine (NE) levels and immunohistochemical analysis of renal cortical axon density.

Results:
At 7 and 28 days, cell disruption in non-target perivascular tissues (ureter, kidney, lymph nodes, skeletal muscle and adrenal glands) were rare/absent, whereas renal artery nerve disruption and axonal loss were sustained through 28 days (Figure). Through 180 days, nerve atrophy due to axonal destruction was apparent within and downstream to the ablation regions. Consistent nerve necrosis at the ablation sites was evident at day 7, but not day 180. Fibrosis was confined to the ablated regions at 7 and 180 days. Renal cortical axon density and corresponding cortical NE levels were significantly reduced at 7 and 180 days in the RF RDN group vs. control.

Conclusion:
RF RDN specifically disrupted the renal nerves around the renal artery leading to downstream axonal loss in the renal cortex. Renal cortical axon density, associated NE reduction, and nerve atrophy due to axonal destruction were sustained through 180 days post-RDN in a normotensive swine model. These results support the existing clinical evidence of specific and durable effects of RF RDN in lowering blood pressure.
PS-BPB07-5: HYPERTENSIVE STIMULI PROMOTE NEUROINFLAMMATION AND COGNITIVE IMPAIRMENT IN A PRESSURE-DEPENDENT MANNER
Authors: Dinh Quynh Nhu , Selvaraji Sharmelee , Lo Cecilia , Vinh Antony , Kim Hyun Ah , Chrissobolis Sophocles , Drummond Grant R , Arumugam Thiruma , Sobey Christopher G , De Silva T Michael 
Published: January 2023

Objective:
Hypertension greatly increases the risk for cognitive impairment, and is associated with inflammation of the brain. However, it is unclear to what extent there is neuroinflammation during hypertension and whether this promotes cognitive impairment. This study aimed to quantify neuroinflammatory and cognitive changes caused by administration of angiotensin II, and determine whether this is blood pressure-dependent.

Design and method:
Male C57Bl/6 mice were administered vehicle (saline; n = 33) or angiotensin II (0.7 mg/kg/d, n = 34) for 14 d via an osmotic minipump. A subset of mice also received hydralazine hydrochloride (50 mg/kg; n = 38) in their drinking water for 14 d after minipump implantation. Systolic blood pressure (SBP) was measured using tail-cuff; inflammation was assessed using flow cytometry and RNA sequencing; and recognition memory was evaluated using the novel object recognition test.

Results:
Angiotensin II infusion increased SBP and promoted accumulation of neutrophils, monocytes, T cells and B cells in the brain compared to vehicle infusion which was blunted by co-administration of hydralazine (n = 7–8, P < 0.05). Angiotensin II infusion also impaired recognition memory and this effect could be prevented by co-treatment with hydralazine (n = 11–12, P < 0.05). Angiotensin II infusion promoted differential expression of 1194 genes in whole brain hemisphere and 634 genes in hippocampus compared to vehicle infusion. Out of these genes, 295 in whole brain hemisphere and 125 in hippocampus were inflammation/immune-related (n = 6, P-adjusted < 0.05). Angiotensin II caused downregulation of genes involved in cognitive function and memory consolidation (Dusp1, Arc) and upregulation of genes involved in immune cell function, regulation and migration (H2-Ab1, H2-Q6, Il17rc, Fcrlb, Ltb, Ccl8, Itga9) in whole brain hemisphere (n = 6, P-adjusted < 0.05). In the hippocampus, a key region in learning and memory, angiotensin II promoted upregulation of genes involved in immune cell proliferation and differentiation (Il12rb2, Acvr1b, Sema3c) and apoptosis (Plxna3, Anxa11, Hyal1, Axin1) (n = 6, P-adjusted < 0.05). Co-treatment with hydralazine altered expression of all of these genes suggesting possible reversal of the transcriptomic changes induced by angiotensin II infusion (n = 6, P-adjusted < 0.05).

Conclusion:
Angiotensin II promotes neuroinflammation and cognitive impairment in a blood pressure-dependent manner. Co-treatment with hydralazine may reverse some of the transcriptomic changes induced by angiotensin II. Chronic neuroinflammation may be a contributing factor to cognitive impairment during hypertension and could be modulated by blood pressure reduction.
PS-BPB07-6: NOVEL HUMORAL AND NEURONAL PATHWAYS FOR DIRECT BLOOD PRESSURE CONTROL BY MACULA DENSA CELLS
Authors: Gyarmati Georgina , Shroff Urvi Nikhil , Deepak Sachin , Izuhara Audrey , PetiPeterdi Janos 
Published: January 2023

Objective:
According to traditional physiological knowledge, macula densa (MD) cells of the juxtaglomerular apparatus (JGA) in the kidney maintain body fluid homeostasis and blood pressure (BP) indirectly by controlling renal and glomerular hemodynamics and renin secretion based on local sensory inputs. However, recently identified microanatomical (long, axon-like basal cell processes, secretory vesicles) and functional (high level of protein synthesis) features of MD cells suggest they perform non-traditional functions. The present study addressed the hypothesis that MD cells can directly and acutely control distant cardiovascular organ functions and blood pressure via novel secreted hormones and communications with renal nerves.

Design and method:
A comprehensive research approach used transgenic mouse models (MD-GFP, MD-Ai27 mice that selectively express the depolarizing channel rhodopsin ChR2 in MD cells), intravital multiphoton imaging, systemic BP monitoring via the cannulated carotid artery, whole mount kidney imaging and 3D analysis, and single-cell transcriptomic analysis.

Results:
Bulk and single cell MD transcriptome analysis identified the high expression of secreted angiogenic and vasoactive factors (Pappa2, Vash2, Cyr61, Aard, Pamr1) and synaptic proteins (Unc5d, Tenm2, Hpcal4, Nsg2, Syp, Syt5, Grin2c, Gabrr2, Begain) with their altered kidney and plasma levels in disease and MD gain and loss-of-function conditions. Immunohistochemistry and 3D tissue volume rendering of optically cleared whole-mount MD-GFP kidneys identified the high MD expression of synaptophysin and the close anatomical association between MD cell basal processes and tyrosin-hydroxylase (TH)+ or calcitonin gene-related peptide (CGRP)+ sympathetic and sensory nerve endings. Optogenetic MD stimulation was induced by blue light (470 nm) exposure of the whole left kidney of MD-Ai27 mice, which maneuver acutely and reversibly increased systemic BP by 22 ± 5mmHg (P < 0.05, n = 5).

Conclusions:
MD cells secrete hormones that target the vasculature and form synapses with sympathetic and sensory renal nerves. These novel MD and JGA pathways may be involved in direct BP control and represent exciting future therapeutic opportunities for renal and cardiovascular disease and hypertension.
PS-BPB08-3: OFF-TARGET EFFECTS OF SLEEVE GASTRECTOMY ON BLOOD PRESSURE INDEPENDENT OF BODY WEIGHT REDUCTION IN DIET-INDUCED OBESITY RATS: ROLE OF CHOLECYSTOKININ
Authors: Yoshida Yuichi , Gotoh Koro , Masaki Takayuki , Ozeki Yoshinori , Miyamoto Shotaro , Okamoto Mitsuhiro , Shibata Hirotaka 
Published: January 2023

Objective:
Sleeve gastrectomy (SG) is currently the most selected surgical bariatric procedure for weight loss by shrinking the stomach. SG has been reported to improve glucose metabolism by altering gastrointestinal hormones, but the details of why blood pressure improves are not known. The purpose of this study is to elucidate the mechanism of why SG lowers blood pressure in diet induced obese rats.

Design and method:
Male Sprague Dawley (SD) rats were subjected to surgical [sham operation (SO) or SG] and dietary interventions [fed a normal diet or high fat diet (HFD) ad libitum or pair fed (PF)]. Diet induced obese rats fed 60% HFD for 12 weeks. Systolic blood pressure (SBP), urinary sodium excretion, and gastrointestinal hormones and renin angiotensin system in renal tissue were examined 4 weeks after surgery. In addition, cholecystokinin (CCK) was administered intraperitoneally to SD rats and evaluated for changes in blood pressure and renal tissue renin angiotensin system.

Results:
Both SG and PF treatments reduced body weight compared with SO. SG exhibited a reduction in SBP compared with PF, which was associated with a reduction in renal renin (536 ± 48.5 U/g kidney and 1385 ± 55.1 U/g kidney, p < 0.01), angiotensin II (Ang II) (48.2 ± 5.8 ng/g kidney and 258.7 ± 16.9 ng/g kidney, p < 0.01), and catechol O methyltransferase (COMT) levels (0.68 ± 0.05 /αtub and 1.34 ± 0.13/αtub, p < 0.01). SG increased plasma CCK levels compared with PF (p < 0.01 for each), whereas GLP1 and PYY were not changed in fasting. SD rats after CCK administration showed decreased SBP (107.7 ± 2.3 mmHg and 118.0 ± 1.8 mmHg, p < 0.01), COMT (0.49 ± 0.04 /GAPDH and 1.11 ± 0.19/GAPDH, p = 0.02), renin (967 ± 71.3 U/g kidney and 1394 ± 90.8 U/g kidney, p < 0.01), and Ang II (598 ± 76.7 ng/g kidney and 874 ± 86.6 ng/g kidney, p = 0.02) in the kidney compared to controls.

Conclusions:
The SG reduced SBP, at least in part, through suppression of the sympathetic nerve action by elevation of CCK which is followed by suppression of the intrarenal renin angiotensin system.

Conclusions:
CCK may have a blood pressure lowering effect, and further research is needed to determine whether CCK can be used as a new antihypertensive agent in the future.
PS-BPB08-7: MECHANISMS OF MINERALOCORTICOID RECEPTOR-ASSOCIATED HYPERTENSION IN DIABETES MELLITUS: ROLE OF O-GLCNAC MODIFICATION
Authors: Jo Rie , Shibata Hirotaka , Kurihara Isao , Yokota Kenichi , Kobayashi Sakiko , Murai-Takeda Ayano , Mitsuishi Yuko , Hayashi Takeshi , Nakamura Toshifumi , Itoh Hiroshi 
Published: January 2023

Objective:
Recently administration of non-steroidal mineralocorticoid receptor (MR) antagonist with maximal tolerable doses of the renin-angiotensin system inhibitors significantly reduced renal as well as cardiovascular composite outcomes in patients with type 2 diabetes and chronic kidney diseases. However, molecular mechanisms of how MR is activated are not understood. Post-translational modification of O-linked-N-acetylglucosamine (O-GlcNAc) has emerged as an essential glucose-sensing mechanism. The aim of this study was to clarify whether MR is modified by O-GlcNAc and figure out the significance of this modification on MR in the context of diabetes mellitus.

Design and method:
1) The MR transcriptional activities were investigated in reporter assays and real time RT-PCR. Levels of expression of MR were examined with western blot analysis. Cells were cultured in 5 mM or 30 mM glucose conditions and additionally treated with PUGNAc, an O-GlcNAcase inhibitor, or 6-diazo-5-oxonorleucine (DON), a glucosamine-fructose-6-phosphate amidotransferase inhibitor. 2) O-GlcNAc modification of MR was investigated with coimmunoprecipitation assays. We mapped actual O-GlcNAc sites on MR by liquid chromatography-tandem mass spectrometry and generated several MR mutants. 3) We evaluated the expression levels of MR and the total O-GlcNAc levels in kidneys of 9-week-old db/db mice. We also intraperitoneally administered 3 g/kg DON to them for five days and evaluated the same subjects.

Results:
1) Treatments with either 30 mM glucose or PUGNAc enhanced 10–10 M aldosterone-mediated MR transactivation by 2-fold and increased endogenous SGK1 mRNA levels. These changes were accompanied by increased expression levels of MR protein. In contrast, treatment with DON lowered a reporter activity and the expression levels of MR. 2) Coimmunoprecipitation assays showed that MR was modified by O-GlcNAc and this modification of MR was increased by 30 mM glucose and PUGNAc treatment. The MR mutant of multiple O-GlcNAc sites (S295A/S296A/S298A/S299A) showed the decrease of its O-GlcNAc level, which was accompanied by lowering their expression levels and transcriptional activities by 40%. 3) The levels of MR protein increased by 2.5-fold in parallel with O-GlcNAc levels in kidneys of db/db mice. In addition, mRNA levels of SGK1 increased by 2-fold in db/db mice. Conversely, administration of DON decreased the expression levels of MR parallel to the total O-GlcNAc levels in kidneys.

Conclusions:
We showed for the first time that MR is a target for O-GlcNAc modification. High glucose conditions enhance O-GlcNAc modification of MR, which are associated with increased MR levels and its transcriptional activities in vitro and in vivo. The epigenetic modification of MR may account for the pathological MR activation in diabetes mellitus.
PS-BPB09-4: ARTERIAL SITES AND SEX DIFFERENCES IN ENHANCING VASORELAXATION RESPONSE BY PERIVASCU-LAR ADIPOSE TISSUE IN METABOLIC SYNDROME RATS
Authors: Kagota Satomi , Futokoro Risa , Fumoto Kana Maruyama , Shinozuka Kazumasa 
Published: January 2023

Objective:
Regulation of arterial tone by perivascular adipose tissue (PVAT) differs with sex. We have demonstrated that PVAT compensates vascular tone when vascular dysfunc-tion occurs in mesenteric arteries of male SHRSP. Z-Leprfa/IzmDmcr (SPZF) rats, but such compensation function disappears in the late stage of metabolic syndrome (MetS). In con-trast, the favorable effects of PVAT remain in female SPZF even after the effects disappear in age-matched males.

Design and method:
Therefore, in this study, we investigated whether the sex differences in PVAT response are observed in another arterial sites in SPZF and in another MetS model, SHR/NDmcr-cp (CP) rats as well. Renal arteries were isolated from male and female SPZF rats and CP rats at 23 weeks of age. Ring preparations with and without PVAT were made. Vasodilation and mRNA transcript levels in PVAT were examined using organ bath methods and quantitative real-time PCR, respectively.

Results, and Conclusions:
In renal arteries without PVAT of SPZF and CP rats, acetylcholine-induced relaxations were smaller in female than in male. The presence of PVAT increased the relaxations in CP rats only. In contrast, sodium nitroprusside-induced relaxations, nevertheless presence or ab-sence of PVAT, were smaller in female than in male in SPZF rats, but sex differences were not observed in CP rats. Apelin mRNA levels in female CP rats were the highest among groups. The enhancements of acetylcholine-induced relaxations by PVAT were positively correlated with apelin mRNA levels in PVAT. These results demonstrated that sex difference in enhancing vasorelaxation response by PVAT in renal arteries differs to that in mesenteric arteries in SPZF rats at the same age and to that in another MetS model strain, CP rats, at the same age and arterial sites. This discrepancy observed in female rats between two MetS strains may be associated with the difference in arterial dysfunction mechanism; namely, impairment of only endothelial nitric oxide production in CP rats, and deterioration of re-sponse to nitric oxide in smooth muscle in SPZF rats. Furthermore, apelin levels of PVAT may be involved in the appearance of modulation of PVAT on arterial tone.
PS-BPB10-1: INVOLVEMENT OF RENAL TUBULAR NFAT5 IN THE REGULATION OF BLOOD PRESSURE AND BODY FLUID VOLUME
Authors: Izumi Yuichiro , Hiramatsu Akiko , Eguchi Koji , Matsuo Naomi , Deng Qinyuan , Inoue Hideki , Nakayama Yushi , Nonoguchi Hiroshi , Aramburu Jose , Rodriguez Cristina Lopez , Kakizoe Yutaka , Adachi Masataka , Kuwabara Takashige , Mitsuyama Shokei Kim , Mukoyama Masashi 
Published: January 2023

Objective:
Nuclear factor of activated T-cells 5 (NFAT5) is an osmoresponsive transcription factor that activates osmoprotective genes to protect cells against hypertonicity. Renal tubular cell-specific NFAT5 knockout (KO) mice have been shown to exhibit polyuria, hypernatremia, low urinary sodium excretion, and increased expression of the epithelial sodium channel (ENaC) in the kidney. In the present study, regulation of blood pressure (BP) as well as that of body fluid volume were examined in the wild type (WT) mice and NFAT5 KO mice.

Methods:
The BP of KO mice and WT mice was measured using radiotelemetry method. The mice were fed with regular salt diet (RSD, 0.3% NaCl chow) or high salt diet (HSD, 8% NaCl chow) followed by the treatment with amiloride, an ENaC blocker. To assess body fluid volume, the plasma renin activity (PRA) and the plasma aldosterone concentration (PAC) were measured at the condition of RSD and HSD, together with plasma arginine vasopressin (AVP) and hematocrit (Ht) levels.

Results:
Compared to WT mice, the mean BP was significantly higher in KO mice both at the condition with RSD and that with HSD in dark period, but not in light period. Treatment with amiloride significantly decreased the mean BP in KO mice with HSD to the level of WT mice with HSD in dark period. PRA, PAC, and AVP levels were not significantly different between in WT and KO mice with RSD. HSD significantly decreased PRA and PAC and tended to increase the AVP level both in WT and KO mice. The Ht level was significantly lower in KO mice than in WT mice regardless of RSD or HSD (WT with RSD, 42.6 ± 0.5%; WT with HSD, 42.8 ± 0.6%; KO with RSD, 38.3 ± 0.4%; KO with HSD, 39.0 ± 0.4%, n = 4).

Conclusions:
The results suggest that the renal tubular cell-specific NFAT5 KO mice exhibit excess body fluid retention induced by sodium reabsorption through ENaC, leading to salt-sensitive hypertension. Such phenotypes seem to be independent of the systemic renin-angiotensin-aldosterone and AVP systems. Renal tubular NFAT5 could integrate urine concentration and sodium reabsorption in the kidney, thus preventing salt-dependent hypertension.
PS-BPC01-2: PREDICTORS AND EFFECTS OF COMORBID ATRIAL FIBRILLATION IN HYPERTENSIVE PATIENTS DUE TO PRIMARY ALDOSTERONISM
Authors: Sakaguchi Shintaro , Okamoto Ryuji , Inoue Chisa , Akao Masaharu , Kamemura Kohei , Takeda Yoshiyu , Ohno Youichi , Inagaki Nobuya , Rakugi Hiromi , Tanabe Akiyo , Tamura Kouichi , Fujita Satoshi , Yano Yutaka , Dohi Kaoru , Naruse Mitsuhide 
Published: January 2023

Objective:
The incidence of atrial fibrillation (AF) and risk of cardiovascular events are reportedly higher in patients with primary aldosteronism (PA) than those with essential hypertension. This study sought to determine independent predictors of comorbid AF and cardiovascular events in PA patients after PA treatment.

Design and method:
This nationwide registration study included PA patients more than 20 years old. Incident cardiovascular events were observed with a mean follow-up of approximately 3 years. A total of 3,654 patients with PA were included at the time of analysis.

Results:
Prevalence of AF was 2.4%. PA patients with AF were older, more frequently male and had longer duration of hypertension than those without AF. No significant difference in basal plasma and adrenal venous aldosterone concentration, renin activity, potassium concentration, confirmatory tests of PA, laterality or surgery rate were seen between groups. Logistic regression analysis showed age, male sex, cardiothoracic ratio, past history of coronary artery disease and heart failure were independent determinants for AF. PA patients with AF showed a higher frequency of cardiovascular events than those without AF (P < 0.001). Multivariate Cox analyses demonstrated AF in addition to duration of hypertension, older age, male sex, hypokalemia and surgery as independent prognostic factors for cardiovascular events (hazard ratio [HR] 1.866, 95% confidence interval [CI] 1.024–3.401, P < 0.05; HR 1.022, 95%CI 1.006–1.039, P < 0.01; HR 1.424, 95%CI 1.043–1.943, P < 0.05; HR 1.027, 95%CI 1.012–1.042, P = 3.2 × 10–4; HR 1.726, 95%CI 1.226–2.430, P < 0.005; HR 1.458, 95%CI 1.041–2.041, P < 0.05, respectively). After PA treatment, incidence of cardiovascular events did not differ significantly between PA patients with AF and essential hypertension patients with AF from the Fushimi registry during follow up after adjusting age, sex and prevalence of hypertension.

Conclusion:
Early diagnosis of PA may prevent AF and other cardiovascular events in PA patients by shortening the duration of hypertension.
PS-BPC01-5: PROGNOSTIC IMPLICATIONS OF MACHINE LEARNING-DERIVED ECHOCARDIOGRAPHIC PHENOTYPES IN ASYMPTOMATIC COMMUNITY HYPERTENSIVE POPULATIONS
Authors: Cai Anping , Zhou Dan , Zhou Yingling , Tang Songtao , Feng Yingqing , Nie Zhiqiang 
Published: January 2023

Objective:
Echocardiogram is commonly used to evaluate cardiac remodeling in hypertension (HTN). However, study on echocardiographic phenotypes and their prognostic implications in HTN is limited. This study aimed to elucidate these aspects.

Method:
A total of 1881 community hypertensive patients without overt cardiovascular disease and severe renal disease (mean age 62.8 years, women 57.9%) were included. Using Two-Step cluster analysis with four conventional echocardiographic variables, two clusters with distinct echocardiographic phenotypes were identified.

Result:
The Cluster 1 (namely mild-remodeling HTN; n = 1492) had low prevalence of enlarged left atrium (LA; 0.9%) and left ventricular hypertrophy (LVH; 16.2%) and better LV diastolic function. They were younger and more likely to be men and had lower comorbid burden. The Cluster 2 (namely severe-remodeling HTN; n = 389) had higher prevalence of enlarged LA (26.0%) and LVH (83.0%) and worse LV diastolic function. They were older and more likely to be women and had higher comorbid burden. After a median follow-up of 4.2 years, compared to the Cluster 1, the Cluster 2 had higher incidence of cardiovascular (4.1% vs 1.7%; P = 0.006) and all-cause (9.8% vs 4.8%; P < 0.001) death, with adjusted hazard ratio (HR) of 2.80 (95% confidence interval [CI] 1.39–5.62; P = 0.004) and 2.04 (95% CI 1.32–3.14; P < 0.001) respectively. Kaplan-Meier curve plotted the cumulative incidence of cardiovascular and all-cause mortality in the Figure 1 Panel A and B.

Conclusion:
In conclusion, these findings indicate that the conventional echocardiographic variables-based algorithm could be helpful to identify asymptomatic community hypertensive patients at risk for cardiovascular and all-cause death. Further studies are needed to develop and validate phenotype-specific prevention and intervention strategies in HTN.