bluuebunny/crossref_metadata_2025_split huggingface dataset:
Abstract 436: Over - Versus Under-Treatment of Older Hypertensives in Canada
Authors: Fodor George , Baker Penelope , Chen Li , Leenen Frans 
Published: March 2022

In a re-analysis of data collected during the 2006 Ontario Survey on the Prevalence and Control of Hypertension (Leenen et al, CMAJ 2008), we focussed on the actual blood pressures in treated and untreated older and middle-aged hypertensives. In the older (60-79 years of age) population of 1,426,752 subjects, using traditional definitions the prevalence of hypertension was 49% compared to 21% in the middle-aged (40-59 years of age) population. Hypertension treatment and control rates were similarly high in middle-aged and older hypertensives at 67% and 64% respectively. 39% of older hypertensives were treated with a single antihypertensive drug, and of these 54% had a systolic BP level of < 130 mmHg, and 23% had a systolic BP < 120 mmHg. Of the 61% treated with combination therapy, 44% had a systolic BP < 120 mmHg. 13% of older hypertensives were untreated, and out of those approximately 90% had Stage 1 hypertension, with ~70% without additional risk factors.
Considering that monotherapy may lower systolic BP by < 10 mmHg, these findings suggest that there may be a major problem of over-diagnosis and/or over-treatment of hypertension in older adults overestimating substantially the actual prevalence of hypertension, creating an unnecessary burden on the health care system and exposing many older subjects to unnecessary risks of drug therapy.
Abstract 606: Soluble Guanylate Cyclase (sGC) Stimulator Reduces The Cardiac And Renal Damage In Angiotensin II (Ang II)-induced Diastolic Heart Failure
Authors: Haase Nadine , Wilck Nicola , Marko Lajos , Heuser Arnd , Brockschnieder Damian , Kretschmer Axel , Stasch Johannes-Peter , Dechend Ralf , Müller Dominik N 
Published: March 2022

Diastolic heart failure (DHF) is estimated to account for approximately 40% of heart failure cases. Due to the high prevalence and high mortality rates, diastolic heart failure represents a major challenge in cardiovascular medicine. The novel therapeutic alternative with NO-independent direct stimulators of sGC has recently been approved for the treatment of pulmonary hypertension.
We analyzed the role of the sGC stimulator BAY 41-8543 in a transgenic rat model of hypertension-induced diastolic heart failure. We used 4 week-old male double transgenic rats harboring both human renin and angiotensinogen genes (dTGRs). At age 7 weeks, dTGR show striking cardiac hypertrophy with fibrosis, severe diastolic dysfunction but preserved systolic function, albuminuria, and renal failure. We compared vehicle-treated dTGR receiving 10% transcutol, 20% cremophor, 70% water, dTGR receiving 3 mg/kg/d BAY 41-8543, and vehicle-treated SD control rats (single oral dose per day for 3 weeks).
Systolic blood pressure increased progressively in vehicle-treated dTGRs compared with SD rats. BAY 41-8543 significantly reduced the blood pressure (197 ± 11 mmHg vehicle vs 133 ± 4 mmHg BAY 41-8543). Treatment with sGC stimulator ameliorated albuminuria (0.3 ± 0.06 mg/8h at week 7) compared with vehicle-treated dTGRs (12.4 ± 2.6 mg/8h at week 7). In addition BAY 41-8543 prevented fibrosis and inflammation in kidney and heart. Cardiac hypertrophy or myocyte size were not reduced by BAY 41-8543 treatment. Cardiac echocardiography and hemodynamic investigations showed that BAY 41-8543 increased ejection fraction and improved diastolic function including speckle tracking and tissue doppler imaging. Programmed electrical stimulation showed a high non-sustained and sustained ventricular tachycardia induction rate in vehicle-treated dTGRs (46%), which was significantly reduced in BAY 41-8543-treated dTGR (11%). Finally, BAY 41-8543 treatment resulted in 100% survival at week 7, whereas 76% of vehicle-treated dTGRs died.
Our data demonstrate that sGC stimulators ameliorate cardiac and renal end-organ damage including electrical remodeling in a transgenic rat model of hypertension-induced DHF. Treatment of DHF with sGC stimulators offers a novel therapeutic potential.
Abstract 624: Lower Than Expected Morbidity Of Transgenic Mice Expressing Rat Tonin After Myocardial Infarction.
Authors: Palomino Jara Zaira , Ribeiro Amanda , Ezequiel Leandro , Dos Santos Fernando , Figueroa Diego , Watanabe Ingrid , Pesquero Jorge , Irigoyen Maria Claudia , Casarini Dulce Elena 
Published: March 2022

Alternative angiotensin II (AngII) formation pathways have been identified. The tonin, capable to act on angiotensinogen (Agt) to form AngII, seems to have a key role in pathophysiological processes resulting from the deleterious effects of AngII. Study with transgenic animals [TGM(rTon’)] over expressing tonin in the brain, heart, kidneys and adrenal glands showed smaller heart weight to body weight index in cardiac hypertrophy, suggesting some cardioprotective state. This unexpected result goes in disagreement with AngII effects. It was seen that other transgenic mice (ACE, renin transgenics) with anticipated increase of AngII level respond with a more severe disease state to any experimental pathophysiological stress. Thus, the aim of this study was to evaluate whether the smaller cardiac index could also mean better functional state. We assessed this question by studying the hemodynamic and neuro-humoral response of TGM(rTon’) mice to 4 months of myocardial ischemia (MI).
Before MI, TGM(rTon’) mice had similar HR and BP variability, 68% of higher sympathetic-vagal balance, 203% increased of adrenal catecholamine concentration and 77% reduced of AngII to Ang1-7 index compared to control group. After the MI, control and TGM(rTon’) animals showed similar infarction area. However, while the MI-control group reduced 62% of its HR variability and increased 27% of its BP variability, the MI-transgenic group did alter neither HR nor BP variability. Catecholamine profile showed 11% increased in the MI-control group while 41% decreased in the MI-transgenic group. The Ang II to Ang-(1-7) ratio was 40% lower in the MI-transgenic group compared to the MI-control. The TGM(rTon’) group respond to myocardial infarction with maintenance of its HR and BP variability indicating a lower prognostic index of morbidity compared to control group. Unchanged variability may be a reflection of counterbalancing processes recruitment, such as increased formation of Ang-(1-7), as seen in the heart.
Abstract 640: RGS2 Deficiency Impairs Renal Hemodynamics and Function
Authors: Osei-Owusu Patrick , Blumer Kendall J 
Published: March 2022

Regulator of G protein signaling 2 (RGS2) regulates signaling by acting as a GTPase-activating protein for Gq/11α and Gi/oα subunits of heterotrimeric G proteins. Certain single nucleotide polymorphisms and loss-of-function mutations of RGS2 have been linked to human hypertension. RGS2 deficiency in the kidney is sufficient to cause hypertension in mice; however, the renal pathophysiological mechanisms are unknown.
Here, we assessed renal hemodynamics and function using renal blood flow (RBF) and glomerular filtration rate (GFR) measurements, and assessment of pressure natriuresis in wild type (WT) and RGS2 null (RGS2-/-) mice. GFR was measured by plasma clearance of FITC-inulin. Pressure natriuresis was determined by increasing renal perfusion pressure (RPP) stepwise by clamping the superior mesenteric and celiac arteries, and abdominal aorta, while total RBF was simultaneously recorded with flow probe.
Baseline GFR was markedly decreased in RGS2-/- mice compared to WT controls (1.8 ± 0.1 vs. 1.1 ± 0.1 ml/min/g kidney weight, p=0.004). Renal conductance was reduced (70 ± 9 vs. 51 ± 3 μl/min/g kidney weight, p=0.006) while renal vascular resistance (RVR; 14.9 ± 2.2 vs. 20.2 ± 1.3 mmHg/ml/min/g kidney weight, p=0.002) was elevated in RGS2-/- compared to WT mice. The absence of RGS2 resulted in decreased sensitivity and magnitude of change in RVR (WT: 11.17 ± 1.94 vs. RGS2-/-: 6.87 ± 0.90 mmHg/ml/min/g) and conductance (WT: -25.69 ± 3.22 vs. RGS2-/-: -13.87 ± 2.40 ml/min/mmHg/g) after a step increase in RPP. The acute pressure-natriuresis curve shifted rightward in RGS2-/- relative to WT, with no change in the slope. Fractional sodium excretion was unaffected by RGS2 deficiency.
We conclude that RGS2 deficiency impairs renal function and autoregulation by increasing renal vascular resistance and reducing effective renal blood flow. The findings provide a new line of evidence for renal vascular dysfunction as a primary cause of hypertension. Mutations or downregulation of RGS2 in the kidney may contribute to human hypertension by causing renal hypoperfusion and decreased GFR. Signaling pathways regulated by RGS2 may provide therapeutic targets in hypertension patients harboring mutations that potentially decrease expression and/or function of RGS2.
Abstract 017: Ang-(1-7) Influences ET-1 Signaling Through MAS: ETBR Interactions: Implications in Pulmonary Hypertension
Authors: Hood Katie Y , Yusuf Hiba , Montezano Augusto C , Findlay Jane E , Santos Robson A , Castro Carlos H , Baillie George S , MacLean Margaret R , Touyz Rhian M 
Published: March 2022

ACE2 and Ang 1-7 have been shown to protect against pulmonary hypertension (PH). Mechanisms remain unclear. Considering the important role of ET-1 in PH pathophysiology and endothelial dysfunction, we asked whether Ang 1-7 influences ET-1 signaling in endothelial cells and whether Ang 1-7 treatment influences the ET-1 system in PH. Human microvascular endothelial cells (HMEC) were stimulated with ET-1 in absence/presence of Ang 1-7 and showed that Ang 1-7 increased preproET-1 mRNA (250%), ET-1 release (125%) and ETBR protein (50%), p<0.05. ET-1 increases in e-selectin mRNA (400%), VCAM-1 protein (38%) and TNFα production (30%) were blocked by Ang 1-7, p<0.05. Pro-inflammatory effects were dependent on NO. Ang 1-7 increased NO production (257%) in a Mas and ETBR-dependent manner. Mas and ETBR interaction was observed by immunoprecipitation. To characterise physical interactions between Mas/ETBR, we utilised novel technology, employing a library of peptides scanning the MasR sequence, to define sites of ETBR binding. Substitution and truncation identified regions on MasR that confer specificity for ETBR binding. Peptide disruptors to prevent Mas/ETBR interaction were used for in vitro validation. We previously demonstrated in HMEC that Ang 1-7 stimulates Akt phosphorylation (180%), an effect inhibited by pre-incubation with peptide disruptors, p<0.05.
To investigate pathophysiological significance of our findings, we investigated whether Ang 1-7 treatment ameliorates PH and whether this is associated with altered ET-1 status. Hypoxia was used to induce PH in mice: normoxic controls (NC), hypoxic PH (HP), normoxic (NA) and hypoxic PH (HA) treated with Ang 1-7 30μg/kg/day. In HP mice, RVSP (18.7 NC vs. 47.6mmHg HP, p<0.05) RVH (0.19 NC vs. 0.28 HP, p<0.01) and ET-1 levels (0.8 NC vs 2.4pg/ml HP, p<0.05) were increased and blocked by Ang 1-7. Hypercontractility and endothelial dysfunction in pulmonary arteries of HP mice was attenuated by Ang 1-7.
These findings indicate that vasoprotective effects of Ang 1-7 may be mediated through MAS:ETBR dimerization. In vivo studies support a relationship between Ang 1-7/MAS and ET-1 systems. In conclusion we have identified a novel link between Ang 1-7 and ET-1 through physical interactions between MAS and ETBR.
Abstract 071: CX3CR1 Deficiency Aggravates Renal Damage in Angiotensin II Induced Hypertensive Kidney Injury
Authors: Wenzel Ulrich , Ahzdahan Erfan , Paust Hajo , Kurts Christian , Rosendahl Alva 
Published: March 2022

A dense network of macrophages and dendritic cells (DCs) expressing the chemokine receptor CX3CR1 populates the kidney. We recently reported that CX3CR1 regulates the abundance of DCs selectively in the kidney and promotes renal inflammation in glomerulonephritis. Given that inflammation plays also an important role in hypertensive renal injury, we hypothesized that CX3CR1 deficiency should attenuate renal injury in hypertension by reducing the number of renal DCs.
Renal injury was induced by unilateral nephrectomy, angiotensin II (Ang II) infusion (1.5 ng/min/g) and salt (0.9% drinking water).

Ang II induced heavy proteinuria (measured as albumin/creatinine ratio in mg/mg) compared to controls (0.1±0.0) and proteinuria was unexpectedly more severe in knockout mice than in wildtype (WT) mice (day 3 after of Ang II infusion: 19.2±5.4 vs. 2.5±0.6 p<0.01, day 14: 32.4±8.5 vs. 9.2±2.6 p<0.05 n=13 and 11 respectively). Histologic evaluation of kidney sections revealed also an increased number of proteinaceous casts and more glomerular injury in knockout mice (casts 1.1±0.3 vs. 0.1±0.1/high power field, glomerular injury score 0.95±0.06 vs. 0.57±0.06, p<0.01). Also plasma cholesterol levels were significantly higher in knockout mice than in WT mice (145±11 vs. 105±6 mg/dl, p<0.01). No difference was found for blood pressure and cardiac injury (hypertrophy, fibrosis, fetal gene expression) between both groups. Flow cytometric analysis revealed that Ang II infusion significantly increased the number of renal CD11c
+
/MHCII
+
DCs in WT (38.5±1.4%, gated on CD45
+
cells) compared to controls (31.8±3.6%, p<0.05). However, a significant decrease of renal DCs was found in hypertensive CX3CR1 deficient mice (15.2±1.5%, p<0.001). In contrast, the number of CD11b
intermediate
/F4/80
high
macrophages was 8 times higher in the kidney of CX3CR1 deficient mice compared to wildtype mice (5.5±1.5 vs.0.9±0.2%, p<0.01). These findings show that CX3CR1 deficiency reduces renal DC numbers and increases numbers of renal macrophages in hypertension. Surprisingly, despite reduced DC numbers, CX3CR1 deficiency increases proteinuria and glomerular injury, thus, CX3CR1 inhibition should be avoided in hypertension because it may promote proteinuria and renal injury.
Abstract 093: Could Spironolactone Be More Effective Than Sympathetic Renal Denervation to Treat True Resistant Hypertension? Preliminary Results From the DENERVHTA Study.
Authors: Oliveras Anna , Armario Pedro , Sans Atxer Laia , Clarà Albert , Vázquez Susana , Vera Maria , Ho Tai Mooi , Faura Anna , Pascual Julio , de la Sierra Alejandro 
Published: March 2022

Aim:
To compare the efficacy and safety between two therapeutic strategies to reduce 24h-SBP in patients with resistant hypertension: renal denervation or the addition of spironolactone.

Methods:
Twenty-one patients with office-SBP ≥150 mmHg and 24h-SBP≥140 mmHg despite receiving ≥3 full-dose antihipertensive drugs, one a diuretic, but without aldosterone antagonists, were randomized to renal denervation (by Simplicity®) or to spironolactone (25-50 mg), as add-on therapy. Changes in both office- (3 averaged readings) and 24h- BP (by Spacelabs®-90207) were evaluated at 6 months. Comparisons between treatment groups were performed using analysis of variance adjusted by age, gender and baseline values.

Results:
mean age was 62.7 ± 7.6 yr; men: 61.9% (13 of 21); diabetes: 47,6% (10 of 21). Mean BMI: 32.3 ± 6.1 Kg/m
2
. Duration of hypertension: 13.4 ± 7.2 yr. Number of antihypertensive drugs: 4,1 ± 0,7. Mean office-BP: 167,5 ± 20,1 / 91,7 ± 12,4 mmHg. Mean 24h-BP: 151,8 ± 9,1 / 81,7 ± 8,4 mmHg. Baseline characteristics were not different between groups (p=NS for all). Comparison between groups of main changes over time is shown in Table.

Reduction of 24h-SBP was higher in the spironolactone group after adjusting by age, sex and baseline 24h-SBP (p=0.016).
Reduction of eGFR was higher in the spironolactone group after adjusting by baseline eGFR (p=0.033).

Conclusions:
1) As compared to renal denervation, spironolactone was more effective to reduce 24h-SBP after 6 months in patients with resistant hypertension. These differences were not significant as regards office-BP.

2) Spironolactone add-on treatment significantly decreased eGFR as compared to renal denervation treatment.
Abstract 115: Hydrochlorothiazide Lowers Systemic Blood Pressure Predominantly Through Vasodilation in Conditions Associated with Vasoconstriction
Authors: Alshahrani Saeed , Rubinstein Jack , Jiang Min , Barone Sharon , Xu Jie , Zahedi Kamyar , Soleimani Manoocher 
Published: March 2022

Thiazide derivatives are specific inhibitors of the Na+_Cl- Co-transporter (NCC) in the kidney distal tubules, and the most commonly used diuretic for the treatment of mild hypertension. The mechanism by which thiazides reduce the blood pressure (i.e. renal vs. extra renal) is not well understood. The blood pressure response to thiazides requires an initial volume loss (averaging about 1.5 kg) since it is not observed in individuals who are ingesting a high-salt diet. The objective of this study was to elucidate the renal and extra renal effects of thiazides. Using NCC deficient mice, we demonstrate that hydrochlorothiazide (HCTZ), a commonly used thiazide derivative, reduces blood pressure in the presence of volume-depletion and augmentation of circulating angiotensin levels but not in mice with normal vascular volume (NCC KO at baseline = 131.6 ± 4.4 vs. NCC KO with HCTZ = 125.8 ± 3.7 mm Hg) vs. (volume depleted NCC KO at baseline = 118.2 ± 4.1 vs. volume depleted NCC KO with HCTZ= 96.37± 4.5 mm Hg; p <0.05). The reduction in blood pressure by HCTZ occurs in the absence of increased salt excretion or urine output, indicating its extra-renal mechanism. Echocardiography demonstrated no significant changes in cardiac index in response to the drop in blood pressure by HCTZ (WT at baseline = 0.639 ± 0.05 vs. WT with HCTZ = 0.590 ± 0.01 ml/min/g) vs. (volume depleted NCC KO at baseline = 0.617± 0.07 vs. volume depleted NCC KO with HCTZ = 0.509 ± 0.04 ml/min/g). The antihypertensive effects of HCTZ were abrogated in the presence of paxilline, a specific blocker of large conductance calcium activated potassium channels (BK channels) in the vascular smooth muscle cell. Western blotting demonstrated enhanced expression of BK channels in vascular system of volume depleted NCC deficient mice vs. WT mice. Our results indicate that systemic vasoconstriction, as observed in volume depleted states, will amplify the extra-renal effects of HCTZ to lower blood pressure through vasodilation irrespective of the status of its renal target NCC.
Patients with congestive heart failure who are on a combination of a loop diuretic and HCTZ are at increased risk of significant hypotension subsequent to the activation of extra-renal effects of HCTZ, specifically when they become volume depleted.
Abstract P033: Acute Intravenous Glucose Injection Inhibits Tubuloglomerular Feedback and Increase Glomerular Filtration Rate
Authors: Zhang Jie , Lu Yan , Wei Jin , Yip Kay-Pong , Liu Ruisheng 
Published: March 2022

Hyperfiltration is considered a risk factor for diabetic nephropathy, but the mechanism for alterations in glomerular filtration rate (GFR) in diabetes has not been clarified. Nitric oxide synthase 1 (NOS1) highly expresses in the macula densa (MD) and NO inhibits tubuloglomerular feedback (TGF). TGF is one of the major mechanisms for glomerular filtration rate (GFR) regulation. It is not clear whether glucose itself filtered into the tubules has any effect on GFR. We hypothesized the glucose enhances NOS1 activity in the MD, which blunts TGF and increases GFR.
First, we measured GRF in conscious mice by plasma FITC-inulin clearance. Three min after an intravenous infusion of 50μl of 4M glucose in wild type mice, GFR was increased by 19.1% from 236±9.7 to 281±13.4 μl/min. Intravenous saline infusion had no effect on GFR.

NO generation by the MD was then measured in isolated perfused juxtaglomerular apparatus with fluorescent probe DAF-2DA. In response to an increase in tubular glucose concentration from 0 to 300 mg/dl, NO production was increased by 78.4%. TGF, assessed in
vivo
by measuring the change in proximal tubular stop flow pressure (Δ) induced by an increase of perfusion rate in late proximal tubules from 0 to 40 nl/min, was significantly blunted from 6.5±0.9 to 5.0±1.6 mmHg when tubular perfusate glucose concentration was increased 0 to 300 mg/dl.

To determine whether the glucose-induced changes were mediated by NOS1 in MD, we repeated the experiments in MD specific NOS1 KO (MD-NOS1KO) mice. Intravenous glucose infusion did not significantly increase GRF (from 203±15.7 to 220±6.9 μl/min) in the KO mice. Elevating glucose content in tubular perfusate did not alter the TGF response (Δ was from 7.8±1.3 to 7.3±2.1 mmHg) in MD-NOS1KO mice. We concluded that increase of tubular glucose concentration increases GFR by inhibiting TGF response, which is mediated by NO production from NOS1 in the MD.
Abstract P163: Endothelin-1 induces Epithelial-Mesenchymal Transition (EMT) in Human Renal Tubular Cells via Activation of RhoA /ROCK Kinase and Inhibition of YAP Pathways
Authors: Seccia Teresa Maria , Caroccia Brasilina , Gioco Francesca , Piazza Maria , Buccella Valentina , Montini Barbara , Guidolin Diego , Guerzoni Eugenia , Pagnin Elisa , Ravarotto Verdiana , Calò Lorenzo , Belloni Anna Sandra , Rossi GianPaolo 
Published: March 2022

We tested the hypothesis that tubulo-interstitial fibrosis (TIF), the final outcome of most kidney diseases, involves activation of epithelial mesenchymal transition (EMT) through angiotensin II- and endothelin-1 (ET-1)-mechanisms.
In a transgenic model of fulminant angiotensin II-dependent hypertension with early prominent renal damage, the TG(mRen2)27 rat (TGRen2), we found that the development of renal damage implied a decrease of the epithelial marker E-cadherin and an increase of the mesenchymal markers alpha SMA and vimentin, which indicated the occurrence of EMT. As treatment with the angiotensin II type 1 receptor antagonist irbesartan, or with the mixed ET-1 receptor antagonist bosentan, prevented these changes an involvement of both angiotensin II and ET-1 in EMT is suggested.
To confirm this contention we exposed HK-2 human kidney tubular cells to ET-1. This showed that ET-1 blunted the expression of E-cadherin, increased that of alpha SMA and vimentin, enhanced the synthesis of collagen, and also the activity of metalloproteinases (MMP). These changes implicated activation of Rho-kinase signaling pathway and de-phosphorylation of Yes-associated protein (YAP).
Hence, ex vivo and in vitro experiments demonstrated that EMT is a fundamental process in the TIF that accompanies the development of angiotensin II-dependent hypertension. Moreover, they suggested that EMT involves ET-1 acting via ETA and ETB receptors through activation of Rho-kinase and de-activation of YAP pathways.