Oxidative stress-induced renal angiotensin AT1 receptor upregulation causes increased stimulation of sodium transporters and hypertension

Reactive oxygen species have emerged as important molecules in cardiovascular dysfunction such as diabetes and hypertension. Recent work has shown that oxidative stress and angiotensin II signaling mutually regulate each other by multiple mechanisms and contribute to the development of hypertension. Most of the known biological actions of angiotensin II can be attributed to AT1 receptors. The present study was carried out to investigate the role of renal AT1 receptor signaling in oxidative stress-mediated hypertension. Male Sprague-Dawley rats received tap water (control) or 30 mM l-buthionine sulfoximine (BSO), an oxidant, with and without 1 mM tempol (an antioxidant) for 2 wk. Compared with control rats, BSO-treated rats exhibited increased oxidative stress and reduced antioxidant levels and developed hypertension. BSO treatment also caused increased renal proximal tubular AT1 receptor protein abundance, message levels, and ligand binding. In these rats, angiotensin II caused significantly higher accumulation of inositol trisphosphate (IP3) and phospholipase C (PLC) activation which was sensitive to blockade by AT1 but not to AT2 antagonist. Also, angiotensin II-mediated, AT1-dependent MAP kinase, Na-K-ATPase, and Na/H exchanger 3 activation was higher in BSO-treated rats than in control rats. Tempol supplementation of BSO-treated rats restored redox status, normalized AT1 receptor expression, and decreased blood pressure. Tempol also normalized the angiotensin II-mediated, AT1-dependent IP3 accumulation and PLC, MAP kinase, Na-K-ATPase, and Na/H exchanger 3 stimulation. These data suggest that oxidative stress leads to AT1 receptor upregulation, which in turn causes overstimulation of sodium transporters and subsequently contributes to sodium retention and hypertension. Tempol, while reducing oxidative stress, normalizes AT1 receptor signaling and decreases blood pressure.

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Abstract 309: Sp-3 But not the NF-kB Transcription Factor Causes the Up-regulation of Angiotensin Type 1 Receptor Expression and Contributes to Hypertension in Aging FBN rats.

Hypertension ◽

10.1161/hyp.64.suppl_1.309 ◽

2014 ◽

Vol 64 (suppl_1) ◽

Author(s):

Mohammad Saleem ◽

Mohammad Asghar

Keyword(s):

Blood Pressure ◽

Transcription Factors ◽

At1 Receptor ◽

Receptor Expression ◽

Receptor Protein ◽

Receptor Function ◽

Receptor Mrna ◽

Hk2 Cells ◽

Angiotensin Type

We recently reported that age-associated oxidative stress is causal to higher renal angiotensin Type 1 (AT1) receptor function and hypertension in aged Fisher 344 X Brown Norway (FBN) rats. We became interested in examining the mechanism of higher AT1 receptor function in the aging kidneys. Adult (3-month) and aging (21 month) FBN rats were subjected to conscious blood pressure measurement by telemetry approach. The levels of AT1 receptor mRNA in the kidney cortex was measured by qRT-PCR while nuclear Sp-3 and NF-kB-p65 redox-sensitive transcription factors were determined by western blotting. We found that blood pressure was higher in aged than in adult rats (adult vs. old: 110±1 vs. 130±1 mmHg) which was associated with higher AT1 receptor mRNA levels (adult vs. old: 1.51±0.72 vs. 7.86±1.03 DU), and nuclear levels of both Sp-3 (adult vs. old: 0.56±.01 vs. 1.54±.02 DU) and NF-kB-p65 (adult vs. old: 0.9±.01 vs. 1.5±0.01 DU). To further delineate whether sp-3 or NF-kB-p65 or both transcription factors are responsible for the up-regulation of AT1 receptor, human kidney (HK2) cells were transfected with Sp-3 and NF-kB-p65 plasmids. We found that Sp-3 plasmid but not NF-κB-p65 plasmid transfection caused an increase in the levels of AT1 receptor protein in HK2 cells (control vs. transfected: 135±22 vs. 235±10 DU). Furthermore, Sp-3 siRNA treatment resulted in the reduction of Sp-3 (control vs. transfected: 136±10 vs. 93±21 DU) and AT1 receptor protein levels (control vs. transfected: 270±38 vs. 172±201 DU) in HK2 cells. Our results suggest that sp-3 but not the NF-κB-p65 is involved in the up-regulation of renal AT1 receptor that may be contributing to hypertension in aging FBN rats.

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SARS-CoV-2 spike protein promotes IL-6 trans-signaling by activation of angiotensin II receptor signaling in epithelial cells

PLoS Pathogens ◽

10.1371/journal.ppat.1009128 ◽

2020 ◽

Vol 16 (12) ◽

pp. e1009128 ◽

Cited By ~ 2

Author(s):

Tapas Patra ◽

Keith Meyer ◽

Lizzie Geerling ◽

T. Scott Isbell ◽

Daniel F. Hoft ◽

...

Keyword(s):

Angiotensin Ii ◽

Epithelial Cells ◽

Inflammatory Response ◽

Protein Expression ◽

Organ Damage ◽

At1 Receptor ◽

Spike Protein ◽

Receptor Protein ◽

Receptor Signaling ◽

Angiotensin Ii Receptor

Cytokine storm is suggested as one of the major pathological characteristics of SARS-CoV-2 infection, although the mechanism for initiation of a hyper-inflammatory response, and multi-organ damage from viral infection is poorly understood. In this virus-cell interaction study, we observed that SARS-CoV-2 infection or viral spike protein expression alone inhibited angiotensin converting enzyme-2 (ACE2) receptor protein expression. The spike protein promoted an angiotensin II type 1 receptor (AT1) mediated signaling cascade, induced the transcriptional regulatory molecules NF-κB and AP-1/c-Fos via MAPK activation, and increased IL-6 release. SARS-CoV-2 infected patient sera contained elevated levels of IL-6 and soluble IL-6R. Up-regulated AT1 receptor signaling also influenced the release of extracellular soluble IL-6R by the induction of the ADAM-17 protease. Use of the AT1 receptor antagonist, Candesartan cilexetil, resulted in down-regulation of IL-6/soluble IL-6R release in spike expressing cells. Phosphorylation of STAT3 at the Tyr705 residue plays an important role as a transcriptional inducer for SOCS3 and MCP-1 expression. Further study indicated that inhibition of STAT3 Tyr705 phosphorylation in SARS-CoV-2 infected and viral spike protein expressing epithelial cells did not induce SOCS3 and MCP-1 expression. Introduction of culture supernatant from SARS-CoV-2 spike expressing cells on a model human liver endothelial Cell line (TMNK-1), where transmembrane IL-6R is poorly expressed, resulted in the induction of STAT3 Tyr705 phosphorylation as well as MCP-1 expression. In conclusion, our results indicated that the presence of SARS-CoV-2 spike protein in epithelial cells promotes IL-6 trans-signaling by activation of the AT1 axis to initiate coordination of a hyper-inflammatory response.

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Renal function and angiotensin AT1 receptor expression in young rats following intrauterine exposure to a maternal low-protein diet

Clinical Science ◽

10.1042/cs20020355 ◽

2003 ◽

Vol 104 (6) ◽

pp. 607-614 ◽

Cited By ~ 113

Author(s):

Vandana SAHAJPAL ◽

Nick ASHTON

Keyword(s):

Blood Pressure ◽

Renal Function ◽

Angiotensin Ii ◽

Filtration Rate ◽

At1 Receptor ◽

Receptor Expression ◽

Protein Diet ◽

Low Protein Diet ◽

Kidney Weight ◽

Low Protein

Recent studies have proposed a link between impaired nephrogenesis, decreased activity of the renin–angiotensin system and the onset of hypertension in rats exposed in the uterus to a maternal low-protein diet. However, there is no detailed information about renal function in this model; hence the aim of the present study was to assess renal function in young (4-week-old) rats exposed in the uterus to a maternal low-protein diet. Pregnant Wistar rats were fed isocalorific diets containing either 18% (normal protein; offspring denoted NP rats) or 9% (low protein; offspring denoted LP rats) (w/w) protein from conception until birth. At 4 weeks of age, male offspring were anaesthetized and prepared for the study of renal function, during which animals received saline alone, a bolus of enalapril (5 mg·kg-1) or a bolus of enalapril followed by an infusion of angiotensin II (30 ng·min-1·kg-1). Under control conditions, renal haemodynamic and tubular function did not differ. However, when challenged with angiotensin II, LP rats responded with a greater decrease in glomerular filtration rate than did NP rats [NP, 2.0±0.2 ml·min-1·g-1 kidney weight (n=9); LP, 1.0±0.2 ml·min-1·g-1 kidney weight (n=5); P<0.05]. Renal electrolyte excretion did not differ. LP rats had significantly fewer glomeruli than NP rats (P<0.01). Renal angiotensin II AT1 receptor expression was increased (P<0.01) by 24% in LP rats. It is concluded that blood pressure may be elevated in LP rats in order to maintain glomerular filtration rate against a background of fewer nephrons. Increased AT1 receptor expression, which may arise as a result of the direct effect of protein restriction or in response to the reported decrease in renal tissue angiotensin II concentration, could also contribute to the elevated blood pressure of this model.

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Angiotensin II induces AT1 receptor upregulation by oxidative stress and activation of AP1 and NF‐κB in two neuronal cell lines

The FASEB Journal ◽

10.1096/fasebj.21.6.a889-d ◽

2007 ◽

Vol 21 (6) ◽

Author(s):

Dongmei Liu ◽

Lie Gao ◽

Shyamal K. Roy ◽

Irving H. Zucker

Keyword(s):

Oxidative Stress ◽

Angiotensin Ii ◽

Cell Lines ◽

Neuronal Cell ◽

At1 Receptor ◽

Neuronal Cell Lines ◽

Receptor Upregulation

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A Subpressor Dose of Angiotensin II Elevates Blood Pressure in a Normotensive Rat Model by Oxidative Stress

Physiological Research ◽

10.33549/physiolres.932738 ◽

2015 ◽

pp. 153-159 ◽

Cited By ~ 1

Author(s):

M. M. GOVENDER ◽

A. NADAR

Keyword(s):

Oxidative Stress ◽

Blood Pressure ◽

Angiotensin Ii ◽

Mrna Expression ◽

Rat Model ◽

Wistar Rat ◽

Control Group ◽

Sod Activity ◽

Male Wistar Rats ◽

Experimental Group

Oxidative stress is an imbalance between free radicals and antioxidants, and is an important etiological factor in the development of hypertension. Recent experimental evidence suggests that subpressor doses of angiotensin II elevate oxidative stress and blood pressure. We aimed to investigate the oxidative stress related mechanism by which a subpressor dose of angiotensin II induces hypertension in a normotensive rat model. Normotensive male Wistar rats were infused with a subpressor dose of angiotensin II for 28 days. The control group was sham operated and infused with saline only. Plasma angiotensin II and H2O2 levels, whole-blood glutathione peroxidase, and AT-1a, Cu/Zn SOD, and p22phox mRNA expression in the aorta was assessed. Systolic and diastolic blood pressures were elevated in the experimental group. There was no change in angiotensin II levels, but a significant increase in AT-1a mRNA expression was found in the experimental group. mRNA expression of p22phox was increased significantly and Cu/Zn SOD decreased significantly in the experimental group. There was no significant change to the H2O2 and GPx levels. Angiotensin II manipulates the free radical-antioxidant balance in the vasculature by selectively increasing O2− production and decreasing SOD activity and causes an oxidative stress induced elevation in blood pressure in the Wistar rat.

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AT1 receptor‐ independent oxidative stress in angiotensin II (Ang II) infused Male Spontaneously Hypertensive Rats (SHR)

The FASEB Journal ◽

10.1096/fasebj.24.1_supplement.605.14 ◽

2010 ◽

Vol 24 (S1) ◽

Author(s):

Kanchan Bhatia ◽

Jennifer C Sullivan

Keyword(s):

Oxidative Stress ◽

Angiotensin Ii ◽

Spontaneously Hypertensive Rats ◽

At1 Receptor ◽

Ang Ii ◽

Hypertensive Rats ◽

Spontaneously Hypertensive

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

AJP Renal Physiology ◽

10.1152/ajprenal.00335.2019 ◽

2019 ◽

Vol 317 (6) ◽

pp. F1656-F1668 ◽

Cited By ~ 2

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.

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Angiotensin II-AT1–receptor signaling is necessary for cyclooxygenase-2–dependent postnatal nephron generation

Kidney International ◽

10.1016/j.kint.2016.11.003 ◽

2017 ◽

Vol 91 (4) ◽

pp. 818-829 ◽

Cited By ~ 11

Author(s):

Stefanie Frölich ◽

Patrick Slattery ◽

Dominique Thomas ◽

Itamar Goren ◽

Nerea Ferreiros ◽

...

Keyword(s):

Angiotensin Ii ◽

At1 Receptor ◽

Cyclooxygenase 2 ◽

Receptor Signaling

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Long-term exercise attenuates blood pressure responsiveness and modulates kidney angiotensin II signalling and urinary sodium excretion in SHR

Journal of the Renin-Angiotensin-Aldosterone System ◽

10.1177/1470320311408750 ◽

2011 ◽

Vol 12 (4) ◽

pp. 394-403 ◽

Cited By ~ 22

Author(s):

Silmara Ciampone ◽

Rafael Borges ◽

Ize P de Lima ◽

Flávia F Mesquita ◽

Elizabeth C Cambiucci ◽

...

Keyword(s):

Blood Pressure ◽

Angiotensin Ii ◽

Exercise Training ◽

Sodium Excretion ◽

Urinary Sodium Excretion ◽

Urinary Sodium ◽

Receptor Expression ◽

Spontaneously Hypertensive ◽

Wistar Kyoto

Observations have been made regarding the effects of long-term exercise training on blood pressure, renal sodium handling and renal renin–angiotensin–aldosterone (RAS) intracellular pathways in conscious, trained Okamoto–Aoki spontaneously hypertensive rats (SHR) and Wistar Kyoto (WKy) normotensive rats, compared with appropriate age-matched sedentary SHR and WKy. To evaluate the influence of exercise training on renal function and RAS, receptors and intracellular angiotensin II (AngII) pathway compounds were used respectively, and lithium clearance and western blot methods were utilised. The current study demonstrated that increased blood pressure in SHR was blunted and significantly reduced by long-term swim training between the ages of 6 and 16 weeks. Additionally, the investigators observed an increased fractional urinary sodium excretion in trained SHR (SHRT) rats, compared with sedentary SHR (SHRS), despite a significantly decreased creatinine clearance (CCr). Furthermore, immunoblotting analysis demonstrated a decreased expression of AT1R in the entire kidney of TSHR rats, compared with SSHR. Conversely, the expression of the AT2R, in both sedentary and trained SHR, was unchanged. The present study may indicate that, in the kidney, long-term exercise exerts a modulating effect on AngII receptor expression. In fact, the present study indicates an association of increasing natriuresis, reciprocal changes in renal AngII receptors and intracellular pathway proteins with the fall in blood pressure levels observed in TSHR rats compared with age-matched SSHR rats.

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