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Journal of Cellular Physiology Jan 2021Angiotensinogen (AGT) is the unique precursor of all angiotensin peptides. Many of the basic understandings of AGT in cardiovascular diseases have come from research... (Review)
Review
Angiotensinogen (AGT) is the unique precursor of all angiotensin peptides. Many of the basic understandings of AGT in cardiovascular diseases have come from research efforts to define its effects on blood pressure regulation. The development of novel techniques targeting AGT manipulation such as genetic animal models, adeno-associated viral approaches, and antisense oligonucleotides made it possible to deeply investigate the relationship between AGT and cardiovascular diseases. In this brief review, we provide contemporary insights into the emerging role of AGT in cardiovascular diseases. In light of the recent progress, we emphasize some newly recognized features and mechanisms of AGT in heart failure, hypertension, atherosclerosis, and cardiovascular risk factors.
Topics: Angiotensinogen; Animals; Blood Pressure; Cardiovascular Diseases; Humans; Oligonucleotides, Antisense
PubMed: 32572956
DOI: 10.1002/jcp.29889 -
Peptides Jun 2022We previously reported that isolated proximal tubules (PT) internalize the precursor protein angiotensinogen and that the Iodine-labeled protein accumulated in the...
We previously reported that isolated proximal tubules (PT) internalize the precursor protein angiotensinogen and that the Iodine-labeled protein accumulated in the nuclear and mitochondrial fractions of the PT cells; however, whether internalization of angiotensinogen occurs in non-renal epithelial cells is unknown. Therefore, the present study assessed the cellular uptake of I-angiotensinogen in human retinal pigment ARPE-19 epithelial cells, a widely utilized cell model for the assessment of retinal injury, inflammation and oxidative stress. ARPE-19 cells, maintained in serum-free media to remove extracellular sources of bovine serum angiotensinogen and renin, were incubated with Iodine-angiotensinogen at 37 °C and revealed the time-dependent uptake of angiotensinogen over 24 h. In contrast, incubation with labelled Ang II, Ang-(1-7) or Ang I revealed minimal cellular uptake. Subcellular fractionation following a 4-hour uptake of I-angiotensinogen revealed that the majority of the labeled protein localized to the nuclear fraction with lower accumulation in the mitochondrial and cytosolic fractions. Finally, we show that addition of angiotensinogen (2 nM) to the ARPE-19 cells increased oxidative stress as assessed by DCF fluorescence that was blocked by pretreatment of the cells with either the NADPH oxidase 1/4 inhibitor GKT137831, apocynin or atorvastatin, but not the AT receptor antagonist losartan. In contrast, treatment of the cells with Angiotensin II at an equivalent dose to angiotensinogen failed to stimulate oxidative stress. We conclude that human retinal pigment cells internalize angiotensinogen to elicit an increase in oxidative stress through a pathway that appears distinct from the Ang II-AT receptor axis.
Topics: Angiotensin II; Angiotensinogen; Epithelial Cells; Humans; Iodine; Oxidative Stress; Receptor, Angiotensin, Type 1; Retinal Pigments
PubMed: 35183655
DOI: 10.1016/j.peptides.2022.170770 -
Medicina Clinica Jun 2024Even though a large number of antihypertensive drugs are suitable for hypertension treatment, some new therapeutic targets are recently under development. Most are... (Review)
Review
Even though a large number of antihypertensive drugs are suitable for hypertension treatment, some new therapeutic targets are recently under development. Most are focused in the treatment of resistant hypertension, added to the drugs currently available for treating such condition. Others have specific particularities in their duration of action, which allows their use once per month or every six months and could become alternatives to the current antihypertensive treatment. Most interesting therapeutic targets are the renin-angiotensin-aldosterone system, through interference with the RNA of the angiotensinogen, the inhibition of brain aminopeptidase III, the inhibition of aldosterone synthase, and new non-steroidal aldosterone receptor antagonists. In addition, dual endothelin receptor antagonists or agonists of the NPR1 receptor, the main effector of natriuretic peptides are other new interesting therapeutic possibilities. In this paper, we review clinical data on the development of the most interesting molecules acting through these new therapeutic targets.
PubMed: 38849267
DOI: 10.1016/j.medcli.2024.03.028 -
Arteriosclerosis, Thrombosis, and... Dec 2023Blood pressure management involves antihypertensive therapies blocking the renin-angiotensin system (RAS). Yet, it might be inadequate due to poor patient adherence or... (Review)
Review
Blood pressure management involves antihypertensive therapies blocking the renin-angiotensin system (RAS). Yet, it might be inadequate due to poor patient adherence or the so-called RAS escape phenomenon, elicited by the compensatory renin elevation upon RAS blockade. Recently, evidence points toward targeting hepatic AGT (angiotensinogen) as a novel approach to block the RAS pathway that could circumvent the RAS escape phenomenon. Removing AGT, from which all angiotensins originate, should prevent further angiotensin generation, even when renin rises. Furthermore, by making use of a trivalent -acetylgalactosamine ligand-conjugated small interfering RNA that specifically targets the degradation of hepatocyte-produced mRNAs in a highly potent and specific manner, it may be possible in the future to manage hypertension with therapy that is administered 1 to 2× per year, thereby supporting medication adherence. This review summarizes all current findings on AGT small interfering RNA in preclinical models, making a comparison versus classical RAS blockade with either ACE (angiotensin-converting enzyme) inhibitors or AT1 (angiotensin II type 1) receptor antagonists and AGT suppression with antisense oligonucleotides. It ends with discussing the first-in-human study with AGT small interfering RNA.
Topics: Humans; Acetylgalactosamine; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Angiotensinogen; Blood Pressure; Hypertension; Renin; Renin-Angiotensin System; RNA, Small Interfering
PubMed: 37855126
DOI: 10.1161/ATVBAHA.123.319897 -
British Journal of Pharmacology Jul 2023All previous rodent models lacking the peptide hormone angiotensin II (Ang II) were hypotensive. A mixed background strain with global deletion of the angiotensinogen...
BACKGROUND AND PURPOSE
All previous rodent models lacking the peptide hormone angiotensin II (Ang II) were hypotensive. A mixed background strain with global deletion of the angiotensinogen gene was backcrossed to the FVB/N background (Agt-KO), a strain preferred for transgenic generation. Surprisingly, the resulting line turned out to be normotensive. Therefore, this study aimed to understand the unique blood pressure regulation of FVB/N mice without angiotensin peptides.
EXPERIMENTAL APPROACH
Acute and chronic recordings of blood pressure (BP) in freely-moving adult mice were performed to establish baseline BP. The pressure responses to sympatholytic and sympathomimetic as well as a nitric oxide inhibitor and donor compounds were used to quantify the neurogenic tone and endothelial function. The role of the renal nerves on baseline BP maintenance was tested by renal denervation. Finally, further phenotyping was done by gene expression analysis, histology and measurement of metabolites in plasma, urine and tissues.
KEY RESULTS
Baseline BP in adult FVB/N Agt-KO was unexpectedly unaltered. As compensatory mechanisms Agt-KO presented an increased sympathetic nerve activity and reduced endothelial nitric oxide production. However, FVB/N Agt-KO exhibited the renal morphological and physiological alterations previously found in mice lacking the production of Ang II including polyuria and hydronephrosis. The hypotensive effect of bilateral renal denervation was blunted in Agt-KO compared to wildtype FVB/N mice.
CONCLUSION AND IMPLICATIONS
We describe a germline Agt-KO line that challenges all previous knowledge on BP regulation in mice with deletion of the classical RAS. This line may represent a model of drug-resistant hypertension because it lacks hypotension.
Topics: Mice; Animals; Angiotensinogen; Blood Pressure; Nitric Oxide; Angiotensin II; Mice, Inbred Strains; Renin-Angiotensin System
PubMed: 36740662
DOI: 10.1111/bph.16051 -
Clinical Science (London, England :... Jan 2021Brain renin-angiotensin system (RAS) activation is thought to mediate deoxycorticosterone acetate (DOCA)-salt hypertension, an animal model for human primary...
Brain renin-angiotensin system (RAS) activation is thought to mediate deoxycorticosterone acetate (DOCA)-salt hypertension, an animal model for human primary hyperaldosteronism. Here, we determined whether brainstem angiotensin II is generated from locally synthesized angiotensinogen and mediates DOCA-salt hypertension. To this end, chronic DOCA-salt-hypertensive rats were treated with liver-directed siRNA targeted to angiotensinogen, the angiotensin II type 1 receptor antagonist valsartan, or the mineralocorticoid receptor antagonist spironolactone (n = 6-8/group). We quantified circulating angiotensinogen and renin by enzyme-kinetic assay, tissue angiotensinogen by Western blotting, and angiotensin metabolites by LC-MS/MS. In rats without DOCA-salt, circulating angiotensin II was detected in all rats, whereas brainstem angiotensin II was detected in 5 out of 7 rats. DOCA-salt increased mean arterial pressure by 19 ± 1 mmHg and suppressed circulating renin and angiotensin II by >90%, while brainstem angiotensin II became undetectable in 5 out of 7 rats (<6 fmol/g). Gene silencing of liver angiotensinogen using siRNA lowered circulating angiotensinogen by 97 ± 0.3%, and made brainstem angiotensin II undetectable in all rats (P<0.05 vs. non-DOCA-salt), although brainstem angiotensinogen remained intact. As expected for this model, neither siRNA nor valsartan attenuated the hypertensive response to DOCA-salt, whereas spironolactone normalized blood pressure and restored brain angiotensin II together with circulating renin and angiotensin II. In conclusion, despite local synthesis of angiotensinogen in the brain, brain angiotensin II depended on circulating angiotensinogen. That DOCA-salt suppressed circulating and brain angiotensin II in parallel, while spironolactone simultaneously increased brain angiotensin II and lowered blood pressure, indicates that DOCA-salt hypertension is not mediated by brain RAS activation.
Topics: Angiotensin II; Angiotensinogen; Animals; Brain; Brain Stem; Desoxycorticosterone Acetate; Hypertension; Male; Rats, Sprague-Dawley; Renin; Renin-Angiotensin System; Sodium Chloride, Dietary; Valsartan; Rats
PubMed: 33404046
DOI: 10.1042/CS20201239 -
The Canadian Journal of Cardiology Dec 2023Despite the availability of various therapeutic classes of antihypertensive drugs, hypertension remains poorly controlled, in part because of poor adherence. Hence,... (Review)
Review
Despite the availability of various therapeutic classes of antihypertensive drugs, hypertension remains poorly controlled, in part because of poor adherence. Hence, there is a need for the development of antihypertensive drugs acting on new targets to improve control of blood pressure. This review discusses novel insights (including the data of recent clinical trials) with regard to interference with the renin-angiotensin system, focusing on the enzymes aminopeptidase A and angiotensin-converting enzyme 2 (ACE2) in the brain, as well as the substrate of renin- angiotensinogen-in the liver. It raises the possibility that centrally acting amino peptidase A inhibitors (eg, firibastat), preventing the conversion of angiotensin II to angiotensin III in the brain, might be particularly useful in African Americans and patients with obesity. Firibastat additionally upregulates brain ACE2, allowing the conversion of angiotensin II to its protective metabolite angiotensin-(1-7). Furthermore, antisense oligonucleotides or small interfering ribonucleic acids suppress hepatic angiotensinogen for weeks to months after 1 injection and thus could potentially overcome adherence issues. Finally, interference with ACE2 ubiquitination is emerging as a future option for the treatment of neurogenic hypertension, given that ubiquitination resistance might upregulate ACE2 activity.
Topics: Humans; Renin-Angiotensin System; Antihypertensive Agents; Glutamyl Aminopeptidase; Angiotensin-Converting Enzyme 2; Angiotensinogen; Angiotensin II; Hypertension; Brain
PubMed: 37348757
DOI: 10.1016/j.cjca.2023.06.013 -
Clinical Science (London, England :... Jul 2021Although the existence of a brain renin-angiotensin system (RAS) had been proposed five decades ago, we still struggle to understand how it functions. The main reason... (Review)
Review
Although the existence of a brain renin-angiotensin system (RAS) had been proposed five decades ago, we still struggle to understand how it functions. The main reason for this is the virtual lack of renin at brain tissue sites. Moreover, although renin's substrate, angiotensinogen, appears to be synthesized locally in the brain, brain angiotensin (Ang) II disappeared after selective silencing of hepatic angiotensinogen. This implies that brain Ang generation depends on hepatic angiotensinogen after all. Rodrigues et al. (Clin Sci (Lond) (2021) 135:1353-1367) generated a transgenic mouse model overexpressing full-length rat angiotensinogen in astrocytes, and observed massively elevated brain Ang II levels, increased sympathetic nervous activity and vasopressin, and up-regulated erythropoiesis. Yet, blood pressure and kidney function remained unaltered, and surprisingly no other Ang metabolites occurred in the brain. Circulating renin was suppressed. This commentary critically discusses these findings, concluding that apparently in the brain, overexpressed angiotensinogen can be cleaved by an unidentified non-renin enzyme, yielding Ang II directly, which then binds to Ang receptors, allowing no metabolism by angiotensinases like ACE2 and aminopeptidase A. Future studies should now unravel the identity of this non-renin enzyme, and determine whether it also contributes to Ang II generation at brain tissue sites in wildtype animals. Such studies should also re-evaluate the concept that Ang-(1-7) and Ang III, generated by ACE2 and aminopeptidase A, respectively, have important functions in the brain.
Topics: Angiotensin II; Brain; Humans; Hypertension; Receptors, Angiotensin; Renin; Renin-Angiotensin System
PubMed: 34291792
DOI: 10.1042/CS20210579 -
Biomolecules Nov 2021The past few decades have seen an increased emphasis on the involvement of the mitochondrial-associated membrane (MAM) in various neurodegenerative diseases,... (Review)
Review
The past few decades have seen an increased emphasis on the involvement of the mitochondrial-associated membrane (MAM) in various neurodegenerative diseases, particularly in Parkinson's disease (PD) and Alzheimer's disease (AD). In PD, alterations in mitochondria, endoplasmic reticulum (ER), and MAM functions affect the secretion and metabolism of proteins, causing an imbalance in calcium homeostasis and oxidative stress. These changes lead to alterations in the translocation of the MAM components, such as IP3R, VDAC, and MFN1 and 2, and consequently disrupt calcium homeostasis and cause misfolded proteins with impaired autophagy, distorted mitochondrial dynamics, and cell death. Various reports indicate the detrimental involvement of the brain renin-angiotensin system (RAS) in oxidative stress, neuroinflammation, and apoptosis in various neurodegenerative diseases. In this review, we attempted to update the reports (using various search engines, such as PubMed, SCOPUS, Elsevier, and Springer Nature) demonstrating the pathogenic interactions between the various proteins present in mitochondria, ER, and MAM with respect to Parkinson's disease. We also made an attempt to speculate the possible involvement of RAS and its components, i.e., AT1 and AT2 receptors, angiotensinogen, in this crosstalk and PD pathology. The review also collates and provides updated information on the role of MAM in calcium signaling, oxidative stress, neuroinflammation, and apoptosis in PD.
Topics: Endoplasmic Reticulum; Humans; Neuroinflammatory Diseases; Parkinson Disease; Renin-Angiotensin System
PubMed: 34827667
DOI: 10.3390/biom11111669 -
Pediatric Nephrology (Berlin, Germany) Nov 2023The current study tested the hypothesis that urinary angiotensinogen (UAGT) and urinary monocyte chemoattractant protein-1 (UMCP-1) levels provide a specific index of...
BACKGROUND
The current study tested the hypothesis that urinary angiotensinogen (UAGT) and urinary monocyte chemoattractant protein-1 (UMCP-1) levels provide a specific index of intrarenal renin-angiotensin system (RAS) status and the degree of infiltration of macrophages associated with RAS blockade and immunosuppressant treatment in pediatric patients with chronic glomerulonephritis.
METHODS
We measured baseline UAGT and UMCP-1 levels to examine the correlation between glomerular injury in 48 pediatric chronic glomerulonephritis patients before treatment. Furthermore, we performed immunohistochemical analysis of angiotensinogen (AGT) and CD68 in 27 pediatric chronic glomerulonephritis patients treated with RAS blockades and immunosuppressants for 2 years. Finally, we examined the effects of angiotensin II (Ang II) on monocyte chemoattractant protein-1 (MCP-1) expression in cultured human mesangial cells (MCs).
RESULTS
Baseline UAGT and UMCP-1 levels positively correlated with urinary protein levels, scores for mesangial hypercellularity, rate of crescentic formation, and expression levels of AGT and CD68 in renal tissues (p < 0.05). UAGT and UMCP-1 levels were significantly decreased after RAS blockade and immunosuppressant treatment (p < 0.01), which was accompanied by AGT and CD68 (p < 0.01), as well as the magnitude of glomerular injury. Cultured human MCs showed increased MCP-1 messenger ribonucleic acid and protein levels after Ang II treatment (p < 0.01).
CONCLUSIONS
The data indicates that UAGT and UMCP-1 are useful biomarkers of the degree of glomerular injury during RAS blockade and immunosuppressant treatment in pediatric patients with chronic glomerulonephritis.
Topics: Humans; Child; Renin-Angiotensin System; Angiotensinogen; Kidney; Chemokine CCL2; Glomerulonephritis; Angiotensin II; Chronic Disease; Immunosuppressive Agents; Macrophages
PubMed: 37231123
DOI: 10.1007/s00467-023-06026-5