scholarly journals Impact of angiotensin II-mediated stimulation of sodium transporters in the nephron assessed by computational modeling

2019 ◽  
Vol 317 (6) ◽  
pp. F1656-F1668 ◽  
Author(s):  
Aurélie Edwards ◽  
Alicia A. McDonough
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Ang Ii ◽  
Sodium Transporters ◽  
Short And Long Term ◽  
Physiological Impact ◽  
Pressure Natriuresis ◽  
Excretion Rates ◽  
Volume Output

Angiotensin II (ANG II) raises blood pressure partly by stimulating tubular Na+ reabsorption. The effects of ANG II on tubular Na+ transporters (i.e., channels, pumps, cotransporters, and exchangers) vary between short-term and long-term exposure. To better understand the physiological impact, we used a computational model of transport along the rat nephron to predict the effects of short- and long-term ANG II-induced transporter activation on Na+ and K+ reabsorption/secretion, and to compare measured and calculated excretion rates. Three days of ANG II infusion at 200 ng·kg−1·min−1 is nonpressor, yet stimulates transporter accumulation. The increase in abundance of Na+/H+ exchanger 3 (NHE3) or activated Na+-K+-2Cl− cotransporter-2 (NKCC2-P) predicted significant reductions in urinary Na+ excretion, yet there was no observed change in urine Na+. The lack of antinatriuresis, despite Na+ transporter accumulation, was supported by Li+ and creatinine clearance measurements, leading to the conclusion that 3-day nonpressor ANG II increases transporter abundance without proportional activation. Fourteen days of ANG II infusion at 400 ng·kg−1·min−1 raises blood pressure and increases Na+ transporter abundance along the distal nephron; proximal tubule and medullary loop transporters are decreased and urine Na+ and volume output are increased, evidence for pressure natriuresis. Simulations indicate that decreases in NHE3 and NKCC2-P contribute significantly to reducing Na+ reabsorption along the nephron and to pressure natriuresis. Our results also suggest that differential regulation of medullary (decrease) and cortical (increase) NKCC2-P is important to preserve K+ while minimizing Na+ retention during ANG II infusion. Lastly, our model indicates that accumulation of active Na+-Cl− cotransporter counteracts epithelial Na+ channel-induced urinary K+ loss.

Abstract P041: Proximal Tubule-specific Deletion Of Angiotensin Ii Type 1a Receptors In The Kidney Lowers Basal Blood Pressure And Attenuates Angiotensin Ii-induced Hypertension By Increasing Glomerular Filtration And The Pressure-natriuresis Response

Hypertension ◽  
2020 ◽  
Vol 76 (Suppl_1) ◽  
Author(s):  
Xiao C Li ◽  
Ana P Leite ◽  
Liang Zhang ◽  
Jia L Zhuo
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Proximal Tubule ◽  
Pressor Response ◽  
Control Group ◽  
Ang Ii ◽  
Induced Hypertension ◽  
Basal Blood Pressure ◽  
Pressure Natriuresis ◽  
Specific Deletion

The present study tested the hypothesis that intratubular angiotensin II (Ang II) and AT 1a receptors in the proximal tubules of the kidney plays an important role in basal blood pressure control and in the development of Ang II-induced hypertension. Mutant mice with proximal tubule-specific deletion of AT 1a receptors in the kidney, PT- Agtr1a -/- , were generated to test the hypothesis. Eight groups (n=7-12 per group) of adult male wild-type (WT) and PT- Agtr1a -/- mice were infused with or without Ang II for 2 weeks (1.5 mg/kg, i.p.). Basal systolic, diastolic, and mean arterial pressures were ~13 ± 3 mmHg lower in PT- Agtr1a -/- than WT mice ( P <0.01). Basal glomerular filtration rate (GFR), as measured using transdermal FITC-sinistrin, was significantly higher in PT- Agtr1a -/- mice (WT: 160.4 ± 7.0 μl/min vs. PT- Agtr1a -/- : 186.0 ± 6.0 μl/min, P <0.05). Basal 24 h urinary Na + excretion (U Na V) was significantly higher in PT- Agtr1a -/- than WT mice ( P <0.01). In response to Ang II infusion, both WT and PT- Agtr1a -/- mice developed hypertension, and the magnitude of the pressor response to Ang II was similar in WT (Δ43 ± 3 mmHg, P <0.01) and PT- Agtr1a -/- mice (Δ39 ± 5 mmHg, P <0.01). However, the absolute blood pressure level was still 16 ± 3 mmHg lower in PT- Agtr1a -/- mice ( P <0.01). Ang II significantly decreased GFR to 132.2 ± 7.0 μl/min in WT mice ( P <0.01), and to 129.4 ± 18.6 μl/min in PT- Agtr1a -/- mice ( P <0.01), respectively. In WT mice, U Na V increased from 139.3 ± 22.3 μmol/24 h in the control group to 196.4 ± 29.6 μmol/24 h in the Ang II-infused group ( P <0.01). In PT- Agtr1a -/- mice, U Na V increased from 172.0 ± 10.2 μmol/24 h in the control group to 264.7 ± 35.4 μmol/24 h in the Ang II-infused group ( P <0.01). The pressor response to Ang II was attenuated, while the natriuretic response was augmented by losartan in WT and PT- Agtr1a -/- mice ( P <0.01). Finally, proximal tubule-specific deletion of AT 1a receptors significantly augmented the pressure-natriuresis response and natriuretic responses to acute saline infusion ( P <0.01) or a 2% high salt diet ( P <0.01). We concluded that deletion of AT 1a receptors selectively in the proximal tubules lowers basal blood pressure and attenuates Ang II-induced hypertension by increasing GFR and promoting the natriuretic response in PT- Agtr1a -/- mice.

Control of sodium excretion by angiotensin II: intrarenal mechanisms and blood pressure regulation

1986 ◽  
Vol 250 (6) ◽  
pp. R960-R972 ◽  
Author(s):  
J. E. Hall
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Arterial Pressure ◽  
Pressure Control ◽  
Ang Ii ◽  
Aldosterone Secretion ◽  
Body Fluid Volume ◽  
Proximal Tubular ◽  
Renal Medullary Blood Flow ◽  
Pressure Natriuresis

Angiotensin II (ANG II) is one of the body's most powerful regulators of Na excretion, operating through extrarenal mechanisms, such as stimulation of aldosterone secretion, as well as intrarenal mechanisms. Considerable evidence suggests that the intrarenal actions of ANG II are quantitatively more important than changes in aldosterone secretion in the normal day-to-day regulation of Na balance and arterial pressure. ANG II at physiological concentrations increases proximal tubular reabsorption, but further studies are needed to determine whether ANG II also has an important effect on more distal tubular segments. ANG II also markedly constricts efferent arterioles, tending to increase Na reabsorption by altering peritubular capillary physical forces and also helping to prevent excessive decreases in glomerular filtration rate. ANG II may also decrease Na excretion and increase urine concentrating ability by reducing renal medullary blood flow. Regulation of Na excretion by ANG II is closely linked with arterial pressure control and volume homeostasis through the renal pressure natriuresis mechanism. Under many physiological conditions, such as changes in Na intake, ANG II greatly multiplies the effectiveness of the pressure natriuresis mechanism to prevent fluctuations in body fluid volume and arterial pressure. In circumstances associated with circulatory depression, such as decreased cardiac function, reductions in blood pressure and increased ANG II formation cause Na retention until arterial pressure is restored to normal. However, in pathophysiological conditions in which ANG II is inappropriately elevated, increased arterial pressure (hypertension) is required for the kidney to "escape" the potent antinatriuretic actions of ANG II and to return Na excretion to normal via the pressure natriuresis mechanism.

Abstract 76: Effects of Long-term Angiotensin-II Infusion on Cardiac and Renal Fibrosis are Blunted in TNFR1-deficient Mice

2015 ◽  
Vol 117 (suppl_1) ◽  
Author(s):  
Magdalena Mayr ◽  
Clemens Duerrschmid ◽  
Dorellyn B Lee ◽  
Guillermo Medrano ◽  
George E Taffet ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Systolic Blood Pressure ◽  
Renal Fibrosis ◽  
Cardiac Fibrosis ◽  
Ang Ii ◽  
Fibrotic Response ◽  
2D Echocardiography ◽  
Collagen Iii

Background: Brief systemic infusion of Angiotensin-II (Ang-II) to wild-type (WT) mice initiates the development of cardiac interstitial fibrosis. Genetic deletion of tumor necrosis factor receptor 1 (TNFR1) obviates this development and concurrently inhibits Ang-II-induced cardiac remodeling and dysfunction. We now investigated long-term effects of Ang-II on the heart, kidney, and cardiorenal function. Methods: WT and TNFR1-KO mice were infused with 1.5 ug/kg/min Ang-II for 1 and 6 weeks (no uninephrectomy or high-salt diet). Heart, kidney, and serum were isolated and evaluated by histology, cytometry, qPCR, and ELISA techniques. Cardiac function was determined by 2D-echocardiography, systolic blood pressure by tail-cuff plethysmography. Results: Brief infusion of Ang-II to WT mice did not evoke a fibrotic response in the kidney. However, after 6 weeks, WT kidneys developed minimal, but significant interstitial collagen deposition which was supported by upregulation of collagen-I, collagen-III, and alpha-smooth muscle actin gene activation. This fibrotic development was associated with the appearance of myeloid fibroblast precursors, pro-inflammatory M1 and pro-fibrotic M2 cells, and myofibroblasts. Transcriptional expression of pro-inflammatory and pro-fibrotic genes was also increased. These changes were not seen in Ang-II-infused TNFR1-KO kidneys. In WT hearts, despite the disappearance of myeloid cells, cardiac fibrosis persisted throughout the 6-week infusion. WT hearts developed clear evidence of accelerated cardiac hypertrophy and remodeling associated with impaired systolic function. Again, these changes were not seen in Ang-II-infused TNFR1-KO hearts. By contrast, both WT and TNFR1-KO mice responded identically with similar elevations of systolic blood pressure, and serum blood urea nitrogen and creatinine levels. Conclusions: Ang-II-infusion induced an immediate fibrotic response in the heart while fibrosis in the kidney developed slowly. The cardiac fibrosis was accompanied by progressive adverse remodeling and worsening of function over time. TNFR1-KO mice were protected from the Ang-II-induced cardiac and renal fibrosis, despite similar increases in blood pressure and renal dysfunction.

Salt sensitivity in hypertensive rats with angiotensin II administration

1990 ◽  
Vol 259 (5) ◽  
pp. R1012-R1016 ◽  
Author(s):  
K. Ando ◽  
Y. Sato ◽  
T. Fujita
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Salt Sensitivity ◽  
Ang Ii ◽  
Short Term ◽  
Salt Loading ◽  
Salt Diet ◽  
Dose Dependent Fashion ◽  
Dose Dependent

We examined the salt sensitivity of blood pressure in angiotensin II (ANG II)-induced hypertension. Wistar rats, salt loaded (0.66, 2, or 8% salt-containing diet) for 4 or 12 days, were infused intravenously with 15 or 60 ng/min of ANG II. Systolic blood pressure (SBP) was not increased by long-term (12 days) salt loading, and SBP was unchanged with ANG II and normal-salt (0.66%) diet. However, when combined with salt loading, ANG II produced hypertension in a dose-dependent fashion; compared with control (120 +/- 2 mmHg), SBP was increased with 15 ng/min of ANG II and 8% salt diet (145 +/- 5 mmHg, P less than 0.05) and with 60 ng/min of ANG II and either 2 or 8% salt diet (149 +/- 8 and 174 +/- 8 mmHg, P less than 0.05, respectively). Na space (exchangeable Na) was increased in a roughly similar pattern and correlated significantly (r = 0.531, P less than 0.05) with SBP. However, with 15 ng/min of ANG II, Na space was not different among rats on either level of salt loading, although the 8% salt diet elevated SBP. Data obtained with short-term (4 days) treatment indicate that an elevated Na space preceded development of hypertension. With 15 ng/min of ANG II and 8% salt diet for 4 days, Na space was markedly (P less than 0.05) increased, but SBP was unchanged.(ABSTRACT TRUNCATED AT 250 WORDS)

scholarly journals Short- and long-term effect of angiotensin II receptor blockade in rats with experimental diabetes.

1993 ◽  
Vol 4 (1) ◽  
pp. 40-49
Author(s):  
A Remuzzi ◽  
N Perico ◽  
C S Amuchastegui ◽  
B Malanchini ◽  
M Mazerska ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Angiotensin Ii ◽  
Systolic Blood Pressure ◽  
Receptor Antagonist ◽  
Diabetic Rats ◽  
Receptor Blockade ◽  
Fractional Clearance ◽  
Short And Long Term ◽  
Normal Controls

The short- and long-term effects of specific angiotensin II (AII) receptor blockade on the evaluation of glomerular injury in moderately hyperglycemic diabetic rats were studied. Three groups of animals were used, a control group, a group of diabetic rats treated with insulin, and a group of insulin-treated diabetic rats receiving the AII receptor antagonist losartan in drinking water. After 4 to 6 wk of observation, diabetic rats showed higher systolic blood pressure and GFR than normal controls. Losartan treatment prevented both systolic blood pressure and GFR rise. Three other groups of rats, similarly treated for a 1-yr period, were used for renal functional and morphologic evaluation. Diabetic animals had higher urinary protein excretion and glomerulosclerosis incidence than did normal controls. Losartan significantly prevented proteinuria and glomerulosclerosis. Evaluation of the sieving properties of the glomerular membrane by Ficoll fractional clearance showed an important increase in the filtration of this marker in diabetic animals, as compared with that in controls, and almost complete prevention of this change in losartan-treated animals. Theoretical analysis of fractional clearance data with a heteroporous model of glomerular size-selectivity showed that in diabetic animals the size of membrane pores was increased uniformly, as compared with that in controls. These changes were completely prevented by the AII receptor antagonist. The results presented here strongly indicate that reduction of AII activity plays a crucial role in the preservation of glomerular structure and function and suggest that the favorable effects previously observed with angiotensin-converting enzyme inhibition in this model depend directly on the reduction of AII activity.

scholarly journals Paleolithic Diet—Effect on the Health Status and Performance of Athletes?

Nutrients ◽  
2021 ◽  
Vol 13 (3) ◽  
pp. 1019
Author(s):  
Barbara Frączek ◽  
Aleksandra Pięta ◽  
Adrian Burda ◽  
Paulina Mazur-Kurach ◽  
Florentyna Tyrała
Keyword(s):  
Blood Pressure ◽  
Body Mass ◽  
Positive Impact ◽  
Model Assessment ◽  
Paleolithic Diet ◽  
Short Term ◽  
Positive Effects ◽  
Short And Long Term ◽  
The Impact

The aim of this meta-analysis was to review the impact of a Paleolithic diet (PD) on selected health indicators (body composition, lipid profile, blood pressure, and carbohydrate metabolism) in the short and long term of nutrition intervention in healthy and unhealthy adults. A systematic review of randomized controlled trials of 21 full-text original human studies was conducted. Both the PD and a variety of healthy diets (control diets (CDs)) caused reduction in anthropometric parameters, both in the short and long term. For many indicators, such as weight (body mass (BM)), body mass index (BMI), and waist circumference (WC), impact was stronger and especially found in the short term. All diets caused a decrease in total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), and triglycerides (TG), albeit the impact of PD was stronger. Among long-term studies, only PD cased a decline in TC and LDL-C. Impact on blood pressure was observed mainly in the short term. PD caused a decrease in fasting plasma (fP) glucose, fP insulin, and homeostasis model assessment of insulin resistance (HOMA-IR) and glycated hemoglobin (HbA1c) in the short run, contrary to CD. In the long term, only PD caused a decrease in fP glucose and fP insulin. Lower positive impact of PD on performance was observed in the group without exercise. Positive effects of the PD on health and the lack of experiments among professional athletes require longer-term interventions to determine the effect of the Paleo diet on athletic performance.

Impact of short- and long-term exposure to air pollution on blood pressure: A two-decade population-based study in Tehran

2021 ◽  
Vol 234 ◽  
pp. 113719
Author(s):  
Alireza Khajavi ◽  
Seyed Saeed Tamehri Zadeh ◽  
Fereidoun Azizi ◽  
Robert D. Brook ◽  
Hengameh Abdi ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Air Pollution ◽  
Population Based ◽  
Population Based Study ◽  
Short And Long Term

scholarly journals Endoplasmic reticulum and oxidant stress mediate nuclear factor-κB activation in the subfornical organ during angiotensin II hypertension

2015 ◽  
Vol 308 (10) ◽  
pp. C803-C812 ◽  
Author(s):  
Colin N. Young ◽  
Anfei Li ◽  
Frederick N. Dong ◽  
Julie A. Horwath ◽  
Catharine G. Clark ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Endoplasmic Reticulum ◽  
Transcription Factor ◽  
Angiotensin Ii ◽  
Er Stress ◽  
Bioluminescence Imaging ◽  
Nuclear Factor Κb ◽  
Nuclear Factor ◽  
Ang Ii ◽  
Arterial Blood

Endoplasmic reticulum (ER) stress and reactive oxygen species (ROS) generation in the brain circumventricular subfornical organ (SFO) mediate the central hypertensive actions of Angiotensin II (ANG II). However, the downstream signaling events remain unclear. Here we tested the hypothesis that angiotensin type 1a receptors (AT1aR), ER stress, and ROS induce activation of the transcription factor nuclear factor-κB (NF-κB) during ANG II-dependent hypertension. To spatiotemporally track NF-κB activity in the SFO throughout the development of ANG II-dependent hypertension, we used SFO-targeted adenoviral delivery and longitudinal bioluminescence imaging in mice. During low-dose infusion of ANG II, bioluminescence imaging revealed a prehypertensive surge in NF-κB activity in the SFO at a time point prior to a significant rise in arterial blood pressure. SFO-targeted ablation of AT1aR, inhibition of ER stress, or adenoviral scavenging of ROS in the SFO prevented the ANG II-induced increase in SFO NF-κB. These findings highlight the utility of bioluminescence imaging to longitudinally track transcription factor activation during the development of ANG II-dependent hypertension and reveal an AT1aR-, ER stress-, and ROS-dependent prehypertensive surge in NF-κB activity in the SFO. Furthermore, the increase in NF-κB activity before a rise in arterial blood pressure suggests a causal role for SFO NF-κB in the development of ANG II-dependent hypertension.

Abstract MP03: ROCK2 Specific Inhibition Attenuates Angiotensin II-induced Hypertension In Mice

Hypertension ◽  
2021 ◽  
Vol 78 (Suppl_1) ◽  
Author(s):  
Daniel J Fehrenbach ◽  
Meena S Madhur
Keyword(s):  
Blood Pressure ◽  
T Cell ◽  
Angiotensin Ii ◽  
Repeated Measures ◽  
Flow Cytometric Analysis ◽  
Coiled Coil ◽  
Ang Ii ◽  
Induced Hypertension

Hypertension, or an elevated blood pressure, is the primary modifiable risk factor for cardiovascular disease, the number one cause of mortality worldwide. We previously demonstrated that Th17 activation and interleukin 17A (IL-17A)/IL-21 production is integral for the full development of a hypertensive phenotype as well as the renal and vascular damage associated with hypertension. Rho-associated coiled-coil containing protein Kinase 2 (ROCK2) serves as a molecular switch upregulating Th17 and inhibiting regulatory T cell (Treg) differentiation. We hypothesize that hypertension is characterized by excessive T cell ROCK2 activation leading to increased Th17/Treg ratios and ultimately end-organ damage. We first showed in vitro that KD025, an experimental orally bioavailable ROCK2 inhibitor inhibits Th17 cell proliferation and IL-17A/IL-21 production. To determine if hypertensive stimuli such as endothelial stretch increases T cell ROCK2 expression, we cultured human aortic endothelial cells exposed to 5% (normotensive) or 10% (hypertensive) stretch with circulating human T cells and HLA-DR+ antigen presenting cells. Hypertensive stretch increased T cell ROCK2 expression 2-fold. We then tested the effect of ROCK2 inhibition with KD025 (50mg/kg i.p. daily) in vivo on angiotensin II (Ang II)-induced hypertension. Treatment with KD025 significantly attenuated the hypertensive response within 1 week of Ang II treatment (systolic blood pressure: 139± 8 vs 108±7mmHg) and this persisted for the duration of the 4 week study reaching blood pressures 20 mmHg lower (135±13mmHg) than vehicle treated mice (158±4mmHg p<0.05 effect of treatment 2-way Repeated Measures ANOVA). Flow cytometric analysis of tissue infiltrating leukocytes revealed that KD025 treatment increased Treg/Th17 ratios in the kidney (0.61±0.03 vs 0.79±0.08, p<0.05 student’s t-test). Thus, T cell ROCK2 may be a novel therapeutic target for the treatment of hypertension.

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