AT1 Receptor Research Articles

A new perspective on the autophagic and non-autophagic functions of the GABARAP protein family: a potential therapeutic target for human diseases.

Mammalian autophagy-related protein Atg8, including the LC3 subfamily and GABARAP subfamily. Atg8 proteins play a vital role in autophagy initiation, autophagosome formation and transport, and autophagy-lysosome fusion. GABARAP subfamily proteins (GABARAPs) share a high degree of homology with LC3 family proteins, and their unique roles are often overlooked. GABARAPs are as indispensable as LC3 in autophagy. Deletion of GABARAPs fails autophagy flux induction and autophagy lysosomal fusion, which leads to the failure of autophagy. GABARAPs are also involved in the transport of selective autophagy receptors. They are engaged in various particular autophagy processes, including mitochondrial autophagy, endoplasmic reticulum autophagy, Golgi autophagy, centrosome autophagy, and dorphagy. Furthermore, GABARAPs are closely related to the transport and delivery of the inhibitory neurotransmitter γ-GABAA and the angiotensin II AT1 receptor (AT1R), tumor growth, metastasis, and prognosis. GABARAPs also have been confirmed to be involved in various diseases, such as cancer, cardiovascular disease, and neurodegenerative diseases. In order to better understand the role and therapeutic potential of GABARAPs, this article comprehensively reviews the autophagic and non-autophagic functions of GABARAPs, as well as the research progress of the role and mechanism of GABARAPs in cancer, cardiovascular diseases and neurodegenerative diseases. It emphasizes the significance of GABARAPs in the clinical prevention and treatment of diseases, and may provide new therapeutic ideas and targets for human diseases. GABARAP and GABARAPL1 in the serum of cancer patients are positively correlated with the prognosis of patients, which can be used as a clinical biomarker, predictor and potential therapeutic target.

Restoration of the gut barrier integrity and restructuring of the gut microbiome in aging by angiotensin-(1-7).

Compromised barrier function of colon epithelium with aging is largely due to gut microbial dysbiosis. Recent studies implicate an important role for angiotensin converting enzymes, ACE and ACE2, angiotensins, and the receptors, AT1 receptor (AT1R) and Mas receptor (MasR), in the regulation of colon functions. The present study tested the hypothesis that leaky gut in aging is associated with an imbalance in ACE2/ACE and that the treatment with angiotenisn-(1-7) (Ang-(1-7)) will restore gut barrier integrity and microbiome. Studies were carried out in Young (3-4 months) and old (20-24 months) male mice. Ang-(1-7) was administered by using osmotic pumps. Outcome measures included expressions of ACE, ACE2, AT1R, and MasR, intestinal permeability by using FITC-dextran, and immunohistochemistry of claudin 1 and occludin, and intestinal stem cells (ISCs). ACE2 protein and activity were decreased in Old group while that of ACE were unchanged. Increased intestinal permeability and plasma levels of zonulin-1 in the Old group were normalized by Ang-(1-7). Epithelial disintegrity, reduced number of goblet cells and ISCs in the old group were restored by Ang-(1-7). Expression of claudin 1 and occludin in the aging colon was increased by Ang-(1-7). Infiltration of CD11b+ or F4/80+ inflammatory cells in the old colons were decreased by Ang-(1-7). Gut microbial dysbiosis in aging was evident by decreased richness and altered beta diversity that were reversed by Ang-(1-7) with increased abundance of Lactobacillus or Lachnospiraceae. The present study shows that Ang-(1-7) restores gut barrier integrity and reduces inflammation in the aging colon by restoring the layer of ISCs and by restructuring the gut microbiome.

Inappropriate activation of the renin-angiotensin system improves cardiac tolerance to ischemia/reperfusion injury in rats with late angiotensin II-dependent hypertension.

The aim of the study was to clarify the role of the interplay between hypertension and the renin-angiotensin system (RAS) in the pathophysiology of myocardial ischemia/reperfusion (I/R) injury. We hypothesized that in the late phase of hypertension with already developed signs of end-organ damage, inappropriate RAS activation could impair cardiac tolerance to I/R injury. Experiments were performed in male Cyp1a1-Ren-2 transgenic rats with inducible hypertension. The early phase of ANG II-dependent hypertension was induced by 5days and the late phase by the 13days dietary indole-3-carbinol (I3C) administration. Noninduced rats served as controls. Echocardiography and pressure-volume analysis were performed, angiotensins' levels were measured and cardiac tolerance to ischemia/reperfusion injury was studied. The infarct size was significantly reduced (by 50%) in 13days I3C-induced hypertensive rats with marked cardiac hypertrophy, this reduction was abolished by losartan treatment. In the late phase of hypertension there are indications of a failing heart, mainly in reduced preload recruitable stroke work (PRSW), but only nonsignificant trends in worsening of some other parameters, showing that the myocardium is in a compensated phase. The influence of the RAS depends on the balance between the vasoconstrictive and the opposed vasodilatory axis. In the initial stage of hypertension, the vasodilatory axis of the RAS prevails, and with the development of hypertension the vasoconstrictive axis of the RAS becomes stronger. We observed a clear effect of AT1 receptor blockade on maximum pressure in left ventricle, cardiac hypertrophy and ANG II levels. In conclusion, we confirmed improved cardiac tolerance to I/R injury in hypertensive hypertrophied rats and showed that, in the late phase of hypertension, the myocardium is in a compensated phase.

GINSENOSIDE-RG3 ENHANCES SOME ANTIHYPERTENSIVE AGENTS-INDUCED INHIBITION OF ADRENAL CATECHOLAMINE SECRETION

Objective: The present study was designed to examine the influence of ginsenoside-Rg3 (Rg3), one of panaxadiol-type saponins, which is isolated from Korean Panax ginseng, in some antihypertensive agents-induced inhibition on the secretion of catecholamines (CA) from the perfused rat adrenal medullae. Design and method: The adrenal gland was isolated and perfused with Krebs-bicarbonate. CA was measured directly by using the fluorospectrophotometer. Results: Ginsenoside-Rg3 (3∼30 μM) during perfusion into an adrenal vein for 90 min significantly inhibited the CA secretion evoked by acetylcholine (ACh). Also, olmesartan (AT1 receptor blocker, 15 μM), simvastatin (an inhibitor of 3-hydroxy-3-methylglutaryl coenzyme A reductase, 60 μM), enalapril (an inhibitor of angiotensin converting enzyme, 150 μM), and cilnidipine (a voltage-dependent L-type Ca2+ channel blocker, 3 μM) significantly reduced the CA secretion evoked by ACh and angiotensin II (Ang II), respectively. In the simultaneous presence of ginsenoside-Rg3 (10 μM) along with four antihypertensive agents (olmesartan, enalapril, simvastatin or cilnidipine), the CA secretion evoked by ACh and Ang II was more strongly inhibited compared with that of each antihypertensive agent-treatment alone. Conclusions: Collectively, these results demonstrate that ginsenoside-Rg3 as well as antihypertensive agents can inhibit the CA secretion evoked by activation of both cholinergic and AT1 receptors from the perfused rat adrenal medulla. When this ginsenoside-Rg3 was used in combination with different antihypertensive agents, their effects of antihypertensive agents on reduction of adrenal CA secretion were significantly enhanced, which may also be clinically beneficial for the treatment of cardiovascular diseases.

GENETIC DELETION OF AT1A RECEPTORS SELECTIVELY IN THE RENOMEDULLARY INTERSTITIAL CELLS OF THE KIDNEY MEDULLA ATTENUATES ANGIOTENSIN II-INDUCED HYPERTENSION

Objective: The present study tested the hypothesis that genetic deletion of angiotensin II (Ang II) AT1 (AT1a) receptors selectively in the renomemdullary interstitial cells (RMICs) of the kidney medulla attenuates the development of Ang II-induced hypertension in mice. Design and method: To test the hypothesis, we used inducible Tenascin-C-CreER2 and Agtr1a-floxed recombination approach to generate a novel mouse model with deletion of AT1a receptors selectively in the RMICs of the kidney (RMIC-Agtr1a-/-). Adult male wildtype (WT) and RMIC-Agtr1a-/- mice (n = 10 per group) were implanted with a telemetry probe and infused with or without Ang II via an osmotic minipump (∼500 μg/kg/day, i.p.) for 2 weeks. Results: Mice with deletion of AT1a receptors selectively in RMICs of the kidney medulla were fertile and grew normally without apparent structural or histological abnormality in the kidney medulla. However, telemetry systolic, diastolic, and mean blood pressure were significantly lower in adult male RMIC-Agtr1a-/- than WT mice (WT: 122 ± 4 mmHg vs. RMIC-Agtr1a-/-: 102 ± 3 mmHg, P < 0.01). Interestingly, this hypotensive phenotype in RMIC-Agtr1a-/- mice was associated with significant decreases in 24 h urine output (WT: 1.56 ± 0.15 mL/24 h vs. RMIC-Agtr1a-/-: 0.98 ± 0.13 mL/24 h, P < 0.01), urinary sodium (WT: 207.9 ± 7.3 μmol/24 h vs. RMIC-Agtr1a-/-: 145.2 ± 5.4 μmol/24 h, P < 0.01), and potassium excretion (WT: 221.0 ± 6.7 μmol/24 h vs. RMIC-Agtr1a-/-: 160.8 ± 10.6 μmol/24 h, P < 0.01), respectively. Moreover, urine osmolality was markedly decreased in RMIC-Agtr1a-/-mice (WT: 1724 ± 335 mOsm/Kg H2O vs. RMIC-Agtr1a-/-: 1128 ± 102 mOsm/Kg H2O, P < 0.01). Ang II infusion significantly increased telemetry systolic blood pressure to 148 ± 5 mmHg in WT mice, but it increased systolic blood pressure only to 129 ± 8 mmHg in RMIC-Agtr1a-/- mice (P < 0.01). Furthermore, infusion of Ang II for 2 weeks failed to restore urine osmolality in RMIC-Agtr1a-/- mice (1226 ± 110 mOsm/Kg H2O, n.s.). Conclusions: In conclusion, the results of the present study support the hypothesis that AT1a receptors in the RMICs of the kidney medulla plays a critical role in maintaining basal blood pressure homeostasis and the development of Ang II-induced hypertension.

INFLUENCE OF CHRONIC AT1 RECEPTOR BLOCKADE ON GASTRIC BARRIER FUNCTION IN MICE

Objective: The AT1 receptor blocker Telmisartan (TEL) is beneficial for the treatment of individuals suffering the Metabolic Syndrome as TEL reveals not only antihypertensive effects but also improves the glucose and lipid control and lowers body weight. As we have recently shown that TEL has impact on gut microbiota and brain barrier function we here investigated whether TEL influences gut barrier function which may participate in decrease of energy intake. Design and method: BL6 mice were fed with chow or high fat diet (45% fat) and were additionally treated with vehicle (CONchow or CONHFD) or TEL (8 mg/kg/d, 12 w, TELchow or TELHFD). Visceral and subcutaneous fat mass was quantified by MRI. Segments of large intestine were Canoy fixed to determine thickness of mucus by immunohistochemistry. PAS staining was performed for depicting goblet cells. The signalling pathway being involved in necroptosis was investigated by Western blots and qPCR. Results: Compared to chow feeding, gain in body weight increased by HFD (3.4±0.5 vs. 14.4g±1.2 g) and was reduced by TEL (1.7±0.5 vs. 2.8±0.5g). Visceral fat and liver mass was higher in CONHFD than CONchow but remained normal by TEL treatment. The mucus thickness was lower in CONHFD than CONchow. Independent on feeding, TEL additionally reduced mucus thickness. Numbers of goblet cells were not affected by HFD feeding and TEL treatment. RIP3 was particularly increased in TELHFD mice, while muc2 and ki67 almost remained unaffected by TEL. Conclusions: In contrast to our expectation, the antiobese effect of TEL was associated with a decrease in mucus thickness. Increase in RIP3 indicates that necroptosis may be enhanced by TEL. Further studies have to be performed to elucidate whether this detrimental TEL effect is true and be relevant for gastrointestinal function.

INHIBITION OF AT1 RECEPTOR PARTIALLY PREVENTS ENDOVASCULAR ETHANOL INJECTION INDUCED ACUTE PULMONARY HYPERTENSION AND SECONDARY PULMONARY ARTERY REMODELING

Objective: Ethanol can induce acute pulmonary hypertension (APH) during endovascular sclerotherapy and embolization. We aimed to examine whether the inhibition of the AT1 receptor can prevent this pathological phenomenon and assess its related mechanisms. Design and method: A total of 40 male swine (age, approximately six months) were selected and performed with absolute ethanol endovascular injection (jugular vein). Saline was used as the negative control. Preventive administration of losartan was conducted orally for 3 consecutive days before operations. Pulmonary arterial pressure (PAP), femoral arterial pressure (FAP), and heart rate (HR) were monitored during procedures. Venous plasma and fresh pulmonary artery (PA) tissue of 32 swine were harvested immediately after the operation. The remaining eight swine were kept and sacrificed one-month after the operations, and PA tissues were harvested for paraffin embedding procedures. Protein level was detected by Western blotting and ELISA, whereas qRT-PCR was used in mRNA detection. H & E staining and immunohistochemistry (IHC) were conducted to evaluate histopathology. Results: Ethanol injection elevated PAP in all swine. The concentration of renin-angiotensin system (RAS) ligands was elevated in plasma (all P < 0.0001) but not in PA. The level of oxidative stress increased in both plasma and PA. MRNA level of AT1R (P < 0.01, 95% CI: 0.251 to 1.006), not AT2R increased in PA. Losartan failed to inhibit APH after all sessions of ethanol injection, and partially reversed the ethanol-induced PA remodeling (1. H & E staining presented abnormal morphology of PA; 2. CD31 IHC staining indicated the intimal hyperplasia; 3. a-SMA IHC staining suggested the pathomorphology of smooth muscle cells; 4. TNF-a IHC staining showed the infiltration of immune cells). The P38 MAPK was activated after ethanol injection and could be inhibited by losartan (P < 0.01, 95% CI: -0.391 to -0.164). Ethanol also promoted the translocation of the P40-PHOX/P47-PHOX/P67-PHOX complex and the activation of NOX, which was independent from RAS. Conclusions: Endovascular ethanol injection can induce AEPAP mainly by activating RAS and P38 MAPK signaling. Losartan can partially prevent AEPAP and vascular remodeling owing to the promotion of NOX activity by ethanol.

GENETIC DELETION OR PHARMACOLOGICAL INHIBITION OF THE SODIUM AND HYDROGEN EXCHANGER 3 IN THE PROXIMAL TUBULES OF THE KIDNEY ATTENUATES ANGIOTENSIN II AND SALT-INDUCED HYPERTENSION

Objective: According to American Heart Association, ∼46% of American adults have hypertension and ∼13 of these patients develop poorly controlled hypertension even treated with >3 - 4 different classes of antihypertensive drugs. The mechanisms underlying poorly controlled hypertension remain incompletely understood. The present study tested the proof of concept hypothesis that the sodium and hydrogen exchanger 3 (NHE3) in the proximal tubules of the kidney may be a therapeutic target of angiotensin II (Ang II) and salt-induced hypertension in mice. Design and method: To test the hypothesis, we generated a new mouse model with deletion of NHE3 selectively in the proximal tubules of the kidney using the iL-Sglt2-Cre and Nhe3-floxed approach (PT-Nhe3-/-). Adult male wildtype (WT) and PT-Nhe3-/- mice were infused without or with a low dose of Ang II (0.5 mg/kg/day, i.p., via minipump) and maintained on 2% high salt diet for 2 weeks to induce Ang II- and salt-dependent hypertension. Animals were then treated without or with an absorbable NHE3 inhibitor AVE-0657 for 2 weeks (20 mg/kg/day, p.o., a gift of Sanofi-Aventis). Results: Under basal conditions, deletion of NHE3 selectively in the proximal tubules of the kidney decreased basal systolic and mean blood pressure by ∼13 ± 3 mmHg in PT-Nhe3-/- mice (P < 0.01 vs. WT), whereas inhibition of NHE3 primarily in the proximal tubules with AVE-0657 lowered basal blood pressure by ∼7 ± 2 mmHg in WT mice (P < 0.05 vs. control WT). Ang II and high salt treatment significantly increased blood pressure by 26 ± 5 mmHg in WT mice (P < 0.01), which was significantly attenuated in PT-Nhe3-/- mice (P < 0.01). Ang II and salt-induced hypertension in WT mice was also significantly attenuated by NHE3 inhibition in the kidney proximal tubules with AVE-0657 (P < 0.01). Concurrent treatment with losartan, an AT1 receptor blocker (20 mg/kg/day, p.o.), completely lowered blood pressure to control level in WT mice (P < 0.05). AVE-0657 had no further effect on blood pressure in PT-Nhe3-/- mice. Conclusions: In conclusion, our results support the proof of concept hypothesis that NHE3 in the proximal tubules of the kidney may be a therapeutic target of Ang II and salt-induced hypertension.

Intracellular Angiotensin II Stimulation of Sodium Transporter Expression in Proximal Tubule Cells via AT1 (AT1a) Receptor-Mediated, MAP Kinases ERK1/2- and NF-кB-Dependent Signaling Pathways.

The current prevailing paradigm in the renin-angiotensin system dictates that most, if not all, biological, physiological, and pathological responses to its most potent peptide, angiotensin II (Ang II), are mediated by extracellular Ang II activating its cell surface receptors. Whether intracellular (or intracrine) Ang II and its receptors are involved remains incompletely understood. The present study tested the hypothesis that extracellular Ang II is taken up by the proximal tubules of the kidney by an AT1 (AT1a) receptor-dependent mechanism and that overexpression of an intracellular Ang II fusion protein (ECFP/Ang II) in mouse proximal tubule cells (mPTC) stimulates the expression of Na+/H+ exchanger 3 (NHE3), Na+/HCO3- cotransporter, and sodium and glucose cotransporter 2 (Sglt2) by AT1a/MAPK/ERK1/2/NF-kB signaling pathways. mPCT cells derived from male wild-type and type 1a Ang II receptor-deficient mice (Agtr1a-/-) were transfected with an intracellular enhanced cyan fluorescent protein-tagged Ang II fusion protein, ECFP/Ang II, and treated without or with AT1 receptor blocker losartan, AT2 receptor blocker PD123319, MEK1/MEK2 inhibitor U0126, NF-кB inhibitor RO 106-9920, or p38 MAP kinase inhibitor SB202196, respectively. In wild-type mPCT cells, the expression of ECFP/Ang II significantly increased NHE3, Na+/HCO3-, and Sglt2 expression (p < 0.01). These responses were accompanied by >3-fold increases in the expression of phospho-ERK1/2 and the p65 subunit of NF-кB (p < 0.01). Losartan, U0126, or RO 106-9920 all significantly attenuated ECFP/Ang II-induced NHE3 and Na+/HCO3- expression (p < 0.01). Deletion of AT1 (AT1a) receptors in mPCT cells attenuated ECFP/Ang II-induced NHE3 and Na+/HCO3- expression (p < 0.01). Interestingly, the AT2 receptor blocker PD123319 also attenuated ECFP/Ang II-induced NHE3 and Na+/HCO3- expression (p < 0.01). These results suggest that, similar to extracellular Ang II, intracellular Ang II may also play an important role in Ang II receptor-mediated proximal tubule NHE3, Na+/HCO3-, and Sglt2 expression by activation of AT1a/MAPK/ERK1/2/NF-kB signaling pathways.

AT1 receptor role in the hypothalamic and renal function interaction

Angiotensin II (ANG II) is involved in renal sodium homeostasis under normal and pathological conditions in close relation with the sympathetic nervous system. Vasopressin, a hormone that modulates renal sodium and water reabsorption, is synthesized and released in the supraoptic and paraventricular nucleus under the influence of ANG II. We hypothesized that brain ANG II (AT1) receptors regulate renal sodium and water reabsorption and excretion through the sympathetic nervous system. In this study, male Wistar rats with renal denervation/sham were fed a hypersodic (4%) or normal (0.4%) diet and evaluated during 5 days in metabolic cages. On day 5, they were injected in the lateral ventricle with an AT1 receptor antagonist, losartan, and sacrificed 12 h later; blood samples and brains were obtained for evaluation. The urine was collected daily. The neuronal activation was analyzed in the nucleus of the supraoptic, paraventricular, subfornical, and organum vasculosum of the lamina terminalis. Activation of vasopressin neurons was evaluated in the supraoptic nucleus. Depending on renal nerve integrity, the hypersodic diet or losartan administration differentially affected neuronal activation. In sham animals, losartan prevented the stimulatory effects induced by the hypersodic diet in water intake and the neuronal activation in vasopressin-positive neurons. Renal denervation modified the effect of the hypersodic diet on water intake, urinary volume, and creatinine excretion, and losartan administration was able to prevent these alterations. Food intake was similar in all groups. Our results suggest that brain AT1 receptors regulate renal sodium and water reabsorption through the sympathetic nervous system in close interaction with vasopressin.

Angiotensin-Related Peptides and Their Role in Pain Regulation.

Angiotensin (Ang)-generating system has been confirmed to play an important role in the regulation of fluid balance and blood pressure and is essential for the maintenance of biological functions. Ang-related peptides and their receptors are found throughout the body and exhibit diverse physiological effects. Accordingly, elucidating novel physiological roles of Ang-generating system has attracted considerable research attention worldwide. Ang-generating system consists of the classical Ang-converting enzyme (ACE)/Ang II/AT1 or AT2 receptor axis and the ACE2/Ang (1-7)/MAS1 receptor axis, which negatively regulates AT1 receptor-mediated responses. These Ang system components are expressed in various tissues and organs, forming a local Ang-generating system. Recent findings indicate that changes in the expression of Ang system components under pathological conditions are involved in the development of neuropathy, inflammation, and their associated pain. Here, we summarized the effects of changes in the Ang system on pain transmission in various organs and tissues involved in pain development process.

Development of a Non-Peptide Angiotensin II Type 1 Receptor Ligand by Structural Modification of Olmesartan as a Biased Agonist.

As a biased agonist, peptide angiotensin II (Ang II) type 1 (AT1) receptor ligand antagonizes Ang II-stimulated G protein signaling but stimulates several kinase pathways. Here, we developed a non-peptide AT1 receptor compound as a biased ligand. We synthesized three non-peptide AT1 receptor ligands (R239470, R781253, and R794847) as candidates of biased ligands. Extracellular signal-regulated kinase (ERK) 1/2 activation and inositol phosphate (IP) production were measured using a cell system that overexpressed AT1 receptors (wild-type, L112A, Q257A, Y292A, and N295A receptors). We also examined the modes of receptor-ligand binding using a competition binding study. The Kd values of R239470, R781253, and R794847 for the AT1 wild-type receptor were 0.8, 21, and 48 nM, respectively, as assessed in a competition binding study. Those of R239470, R781253, and R794847 for the L112A receptor were 37, 23, and 31 nM, respectively. R781253 and R794847 decreased and increased IP production, respectively, whereas R239470 did not change IP production. R781253 and R794847, but not R239470, activated ERK1/2. In conclusion, R239470, R781253, and R794847 act as a neutral antagonist, an inverse agonist, and an agonist with regard to IP production, respectively. On the other hand, R781253 and R794847, but not R239470, are agonists toward ERK1/2 activation. Thus, we developed a non-peptide AT1 receptor compound as a biased ligand.

Gαq protein-biased ligand of angiotensin II type 1 receptor mediates myofibroblast differentiation through TGF-β1/ERK axis in human cardiac fibroblasts

Angiotensin II receptors are members of G protein-coupled receptor superfamily that manifest biased signals toward G protein- and β-arrestin-dependent pathways. However, the role of angiotensin II receptor-biased ligands and the mechanisms underlying myofibroblast differentiation in human cardiac fibroblasts have not been fully elucidated. Our results demonstrated that antagonism of angiotensin II type 1 receptor (AT1 receptor) and blockade of Gαq protein suppressed angiotensin II (Ang II)-induced fibroblast proliferation, overexpression of collagen I and α-smooth muscle actin (α-SMA), and stress fibre formation, indicating the AT1 receptor/Gαq axis is necessary for fibrogenic effects of Ang II. Stimulation of AT1 receptors by their Gαq-biased ligand (TRV120055), but not β-arrestin-biased ligand (TRV120027), substantially exerted fibrogenic effects at a level similar to that of Ang II, suggesting that AT1 receptor induced cardiac fibrosis in a Gαq-dependent and β-arrestin-independent manner. Valsartan prevented TRV120055-mediated fibroblast activation. TRV120055 mediated the upregulation of transforming growth factor-beta1 (TGF-β1) through the AT1 receptor/Gαq cascade. In addition, Gαq protein and TGF-β1 were necessary for ERK1/2 activation induced by Ang II and TRV120055. Collectively, TGF-β1 and ERK1/2 are downstream effectors of the Gαq-biased ligand of AT1 receptor for the induction of cardiac fibrosis.

High salt induces cognitive impairment via the interaction of the angiotensin II-AT1 and prostaglandin E2-EP1 systems.

High salt (HS) intake has been associated with hypertension and cognitive impairment. It is well known that the angiotensin II (Ang II)-AT1 receptor and prostaglandin E2 (PGE2)-EP1 receptor systems are involved in hypertension and neurotoxicity. However, the involvement of these systems in HS-mediated hypertension and emotional and cognitive impairments remains unclear. Mice were loaded with HS solution (2% NaCl drinking water) for 12 weeks, and blood pressure was monitored. Subsequently, effects of HS intake on emotional and cognitive function and tau phosphorylation in the prefrontal cortex (PFC) and hippocampus (HIP) were investigated. The involvement of Ang II-AT1 and PGE2-EP1 systems in HS-induced hypertension and neuronal and behavioural impairments was examined by treatment with losartan, an AT1 receptor blocker (ARB), or EP1 gene knockout. We demonstrate that hypertension and impaired social behaviour and object recognition memory following HS intake may be associated with tau hyperphosphorylation, decreased phosphorylation of Ca2+ /calmodulin-dependent protein kinase II (CaMKII), and postsynaptic density protein 95 (PSD95) expression in the PFC and HIP of mice. These changes were blocked by pharmacological treatment with losartan or EP1 receptor gene knockout. Our findings suggest that the interaction of Ang II-AT1 receptor and PGE2-EP1 receptor systems could be novel therapeutic targets for hypertension-induced cognitive impairment.

Sacubitril/valsartan reduces susceptibility to atrial fibrillation by improving atrial remodeling in spontaneously hypertensive rats

AimSacubitril/valsartan (Sac/Val, LCZ696), the world's first angiotensin receptor-neprilysin inhibitor (ARNi), has been widely used in the treatment of heart failure. However, the use of Sac/Val in the treatment of atrial fibrillation (AF), especially AF with hypertension, has been less reported. We investigated the effect of Sac/Val on atrial remodeling and hypertension-related AF. MethodsThe AF induction rate and electrophysiological characteristics of spontaneously hypertensive rats (SHRs) treated with Sac/Val or Val were detected by rapid atrial pacing and electrical mapping/optical mapping. The whole-cell patch-clamp and Western blot were used to observe electrical/structural remodeling of atrial myocytes/tissue of rats and atrium-derived HL-1 cells cultured under 40 mmHg in vitro. ResultsSac/Val was superior to Val in reducing blood pressure, myocardial hypertrophy and susceptibility of AF in SHRs. The shorten action potentials duration (APD), decreased L type calcium channel current (ICa,L) and Cav1.2, increased ultrarapid delayed rectified potassium current (Ikur) and Kv1.5 in atrial myocytes/tissue of SHRs could be better improved by Sac/Val, as well as the levels of atrial fibrosis. While the protein expression of angiotensin-converting enzyme-1 (ACE-1), angiotensin, angiotensin II type I AT1 receptor (AT1R) and neprilysin (NEP) were increased, which could be more effective ameliorated by Sac/Val than Val. Furthermore, Val + Sacubitrilat (LBQ657) (an active NEP inhibitor) was also superior to LBQ657 or Val in improving the electrical and structural remodeling of HL-1 cells through inhibiting NEP. ConclusionSac/Val can improve atrial structural and electrical remodeling induced by hypertension and reduce the AF susceptibility by inhibiting RAS and NEP. The above effects of Sac/Val were superior to Val alone.

Renin-Angiotensin System and Sex Differences in COVID-19: A Critical Assessment.

The current epidemic of corona virus disease (COVID-19) has resulted in an immense health burden that became the third leading cause of death and potentially contributed to a decline in life expectancy in the United States. The severe acute respiratory syndrome-related coronavirus-2 binds to the surface-bound peptidase angiotensin-converting enzyme 2 (ACE2, EC 3.4.17.23) leading to tissue infection and viral replication. ACE2 is an important enzymatic component of the renin-angiotensin system (RAS) expressed in the lung and other organs. The peptidase regulates the levels of the peptide hormones Ang II and Ang-(1-7), which have distinct and opposing actions to one another, as well as other cardiovascular peptides. A potential consequence of severe acute respiratory syndrome-related coronavirus-2 infection is reduced ACE2 activity by internalization of the viral-ACE2 complex and subsequent activation of the RAS (higher ratio of Ang II:Ang-[1-7]) that may exacerbate the acute inflammatory events in COVID-19 patients and possibly contribute to the effects of long COVID-19. Moreover, COVID-19 patients present with an array of autoantibodies to various components of the RAS including the peptide Ang II, the enzyme ACE2, and the AT1 AT2 and Mas receptors. Greater disease severity is also evident in male COVID-19 patients, which may reflect underlying sex differences in the regulation of the 2 distinct functional arms of the RAS. The current review provides a critical evaluation of the evidence for an activated RAS in COVID-19 subjects and whether this system contributes to the greater severity of severe acute respiratory syndrome-related coronavirus-2 infection in males as compared with females.

Selenium deficiency causes hypertension by increasing renal AT1 receptor expression via GPx1/H2O2/NF-κB pathway.

Epidemiological studies show an association between low body selenium and the risk of hypertension. However, whether selenium deficiency causes hypertension remains unknown. Here, we report that Sprague-Dawley rats fed a selenium-deficient diet for 16 weeks developed hypertension, accompanied with decreased sodium excretion. The hypertension of selenium-deficient rats was associated with increased renal angiotensin II type 1 receptor (AT1R) expression and function that was reflected by the increase in sodium excretion after the intrarenal infusion of the AT1R antagonist candesartan. Selenium-deficient rats had increased systemic and renal oxidative stress; treatment with the antioxidant tempol for 4 weeks decreased the elevated blood pressure, increased sodium excretion, and normalized renal AT1R expression. Among the altered selenoproteins in selenium-deficient rats, the decrease in renal glutathione peroxidase 1 (GPx1) expression was most prominent. GPx1, via regulation of NF-κB p65 expression and activity, was involved in the regulation of renal AT1R expression because treatment with dithiocarbamate (PDTC), an NF-κB inhibitor, reversed the up-regulation of AT1R expression in selenium-deficient renal proximal tubule (RPT) cells. The up-regulation of AT1R expression with GPx1 silencing was restored by PDTC. Moreover, treatment with ebselen, a GPX1 mimic, reduced the increased renal AT1R expression, Na+-K+-ATPase activity, hydrogen peroxide (H2O2) generation, and the nuclear translocation of NF-κB p65 protein in selenium-deficient RPT cells. Our results demonstrated that long-term selenium deficiency causes hypertension, which is due, at least in part, to decreased urine sodium excretion. Selenium deficiency increases H2O2 production by reducing GPx1 expression, which enhances NF-κB activity, increases renal AT1R expression, causes sodium retention and consequently increases blood pressure.

Cardiovascular and renoprotective effects of renal denervation associated with AT1 receptor antagonism in experimental chronic kidney disease

Chronic kidney disease (CKD) is characterized by progressive and irreversible loss of kidney function. The main causes of CKD are arterial hypertension (AH) and type 2 diabetes. Previous studies by our group showed that renal denervation (DNx) decreased arterial hypertension and sympathetic overactivity in rats with CKD. In the present study, we studied the renoprotective and cardiovascular effects of DNx associated or not with renin-angiotensin system (RAS) blockade. Wistar rats underwent experimental CKD induction (⅚ nephrectomy model). After 4 weeks of CKD induction, we performed DNx and collected data after 4 weeks. Groups that underwent RAS blockade were treated orally with losartan (30mg/kg/day) in the last 4 weeks of the 8-week protocol. Losartan decreased arterial pressure (118±21 mmHg) compared to CKD group (175±18 mmHg). However, the association of losartan treatment with DNx was able to normalize this parameter (94±9mmHg). In addition, losartan normalized baseline renal sympathetic nerve activity, and DNX associated or not with losartan normalized splanchnic sympathetic nerve activity. Interestingly, lipocalin associated with neutrophil gelatinase (NGAL), an important marker of tubular injury, and an intrarenal RAS marker were normalized after DNx associated with losartan treatment (70.9±23.8 NGAL:Cru) or not (66.6±17.8 NGAL:Cru) was normalized. Treatments unchanged water intake or urinary flow. Taken altogether, our data show that despite the association of DNx and RAS blockade produces a further decrease in AH, the improvement in renal function markers and normalization in intrarenal RAS and sympathetic drive is similar after DNx or RAS blockade alone. FINANCIAL SUPPORT: CAPES, FAPESP and CNPq This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Angiotensin receptors in GtoPdb v.2023.1

The actions of angiotensin II (Ang II) are mediated by AT1 and AT2 receptors (nomenclature as agreed by the NC-IUPHAR Subcommittee on Angiotensin receptors [63, 155]), which have around 30% sequence similarity. The decapeptide angiotensin I, the octapeptide angiotensin II and the heptapeptide angiotensin III are endogenous ligands. losartan, candesartan, olmesartan, telmisartan, etc. are clinically used AT1 receptor blockers.

Preeclamptic programming unevenly perturbs inflammatory and renal vasodilatory outcomes of endotoxemia in rat offspring: modulation by losartan and pioglitazone.

Introduction: Preeclampsia (PE) enhances the vulnerability of adult offspring to serious illnesses. The current study investigated whether preeclamptic fetal programming impacts hemodynamic and renal vasodilatory disturbances in endotoxic adult offspring and whether these interactions are influenced by antenatal therapy with pioglitazone and/or losartan. Methods: PE was induced by oral administration of L-NAME (50mg/kg/day) for the last 7 days of pregnancy. Adult offspring was treated with lipopolysaccharides (LPS, 5mg/kg) followed 4-h later by hemodynamic and renovascular studies. Results: Tail-cuff measurements showed that LPS decreased systolic blood pressure (SBP) in male, but not female, offspring of PE dams. Moreover, PE or LPS reduced vasodilations elicited by acetylcholine (ACh, 0.01-7.29nmol) or N-ethylcarboxamidoadenosine (NECA, 1.6-100nmol) in perfused kidneys of male rats only. The latter effects disappeared in LPS/PE preparations, suggesting a postconditioning action for LPS against renal manifestation of PE. Likewise, elevations caused by LPS in serum creatinine and inflammatory cytokines (TNFα and IL-1β) as well as in renal protein expression of monocyte chemoattractant protein-1 (MCP-1) and AT1 receptors were attenuated by the dual PE/LPS challenge. Gestational pioglitazone or losartan reversed the attenuated ACh/NECA vasodilations in male rats but failed to modify LPS hypotension or inflammation. The combined gestational pioglitazone/losartan therapy improved ACh/NECA vasodilations and eliminated the rises in serum IL-1β and renal MCP-1 and AT1 receptor expressions. Conclusion: Preeclamptic fetal programming of endotoxic hemodynamic and renal manifestations in adult offspring depends on animal sex and specific biological activity and are reprogrammed by antenatal pioglitazone/losartan therapy.