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Current Hypertension Reports Mar 2020Megalin is well known for its role in the reabsorption of proteins from the ultrafiltrate. Recent studies suggest that megalin also reabsorbs renin and angiotensinogen.... (Review)
Review
PURPOSE OF REVIEW
Megalin is well known for its role in the reabsorption of proteins from the ultrafiltrate. Recent studies suggest that megalin also reabsorbs renin and angiotensinogen. Indeed, without megalin urinary renin and angiotensinogen levels massively increase, and even prorenin becomes detectable in urine.
RECENT FINDINGS
Intriguingly, megalin might also contribute to renal angiotensin production, as evidenced from studies in megalin knockout mice. This review discusses these topics critically, concluding that urinary renin-angiotensin system components reflect diminished reabsorption rather than release from renal tissue sites and that alterations in renal renin levels or megalin-dependent signaling need to be ruled out before concluding that angiotensin production at renal tissue sites is truly megalin dependent. Future studies should evaluate megalin-mediated renin/angiotensinogen transcytosis (allowing interstitial angiotensin generation), and determine whether megalin prefers prorenin over renin, thus explaining why urine normally contains no prorenin.
Topics: Angiotensin II; Angiotensinogen; Animals; Humans; Hypertension; Kidney; Low Density Lipoprotein Receptor-Related Protein-2; Mice; Renin; Renin-Angiotensin System
PubMed: 32172431
DOI: 10.1007/s11906-020-01037-1 -
Clinical Science (London, England :... Jun 2023Compromised barrier function of colon epithelium with aging is largely due to gut microbial dysbiosis. Recent studies implicate an important role for angiotensin...
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.
Topics: Mice; Male; Animals; Gastrointestinal Microbiome; Angiotensin-Converting Enzyme 2; Dysbiosis; Claudin-1; Occludin; Angiotensin I; Peptidyl-Dipeptidase A; Peptide Fragments; Aging; Angiotensin II
PubMed: 37254732
DOI: 10.1042/CS20220904 -
Translational Neurodegeneration Apr 2024The renin-angiotensin system (RAS) was classically considered a circulating hormonal system that regulates blood pressure. However, different tissues and organs,... (Review)
Review
The renin-angiotensin system (RAS) was classically considered a circulating hormonal system that regulates blood pressure. However, different tissues and organs, including the brain, have a local paracrine RAS. Mutual regulation between the dopaminergic system and RAS has been observed in several tissues. Dysregulation of these interactions leads to renal and cardiovascular diseases, as well as progression of dopaminergic neuron degeneration in a major brain center of dopamine/angiotensin interaction such as the nigrostriatal system. A decrease in the dopaminergic function induces upregulation of the angiotensin type-1 (AT1) receptor activity, leading to recovery of dopamine levels. However, AT1 receptor overactivity in dopaminergic neurons and microglial cells upregulates the cellular NADPH-oxidase-superoxide axis and Ca release, which mediate several key events in oxidative stress, neuroinflammation, and α-synuclein aggregation, involved in Parkinson's disease (PD) pathogenesis. An intraneuronal antioxidative/anti-inflammatory RAS counteracts the effects of the pro-oxidative AT1 receptor overactivity. Consistent with this, an imbalance in RAS activity towards the pro-oxidative/pro-inflammatory AT1 receptor axis has been observed in the substantia nigra and striatum of several animal models of high vulnerability to dopaminergic degeneration. Interestingly, autoantibodies against angiotensin-converting enzyme 2 and AT1 receptors are increased in PD models and PD patients and contribute to blood-brain barrier (BBB) dysregulation and nigrostriatal pro-inflammatory RAS upregulation. Therapeutic strategies addressed to the modulation of brain RAS, by AT1 receptor blockers (ARBs) and/or activation of the antioxidative axis (AT2, Mas receptors), may be neuroprotective for individuals with a high risk of developing PD or in prodromal stages of PD to reduce progression of the disease.
Topics: Animals; Humans; Angiotensin Receptor Antagonists; Angiotensins; Blood Pressure; Brain; Dopamine; Parkinson Disease; Receptor, Angiotensin, Type 1; Renin-Angiotensin System
PubMed: 38622720
DOI: 10.1186/s40035-024-00410-3 -
Family Practice Mar 2023Concerns have been raised that angiotensin-converting enzyme-inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) might facilitate transmission of severe acute...
BACKGROUND
Concerns have been raised that angiotensin-converting enzyme-inhibitors (ACE-I) and angiotensin receptor blockers (ARBs) might facilitate transmission of severe acute respiratory syndrome coronavirus 2 leading to more severe coronavirus disease (COVID-19) disease and an increased risk of mortality. We aimed to investigate the association between ACE-I/ARB treatment and risk of death amongst people with COVID-19 in the first 6 months of the pandemic.
METHODS
We identified a cohort of adults diagnosed with either confirmed or probable COVID-19 (from 1 January to 21 June 2020) using computerized medical records from the Oxford-Royal College of General Practitioners (RCGP) Research and Surveillance Centre (RSC) primary care database. This comprised 465 general practices in England, United Kingdom with a nationally representative population of 3.7 million people. We constructed mixed-effects logistic regression models to quantify the association between ACE-I/ARBs and all-cause mortality among people with COVID-19, adjusted for sociodemographic factors, comorbidities, concurrent medication, smoking status, practice clustering, and household number.
RESULTS
There were 9,586 COVID-19 cases in the sample and 1,463 (15.3%) died during the study period between 1 January 2020 and 21 June 2020. In adjusted analysis ACE-I and ARBs were not associated with all-cause mortality (adjusted odds ratio [OR] 1.02, 95% confidence interval [CI] 0.85-1.21 and OR 0.84, 95% CI 0.67-1.07, respectively).
CONCLUSION
Use of ACE-I/ARB, which are commonly used drugs, did not alter the odds of all-cause mortality amongst people diagnosed with COVID-19. Our findings should inform patient and prescriber decisions concerning continued use of these medications during the pandemic.
Topics: Adult; Humans; Angiotensin-Converting Enzyme Inhibitors; Angiotensin Receptor Antagonists; Cohort Studies; COVID-19; Angiotensins; Hypertension
PubMed: 36003039
DOI: 10.1093/fampra/cmac094 -
Journal of Human Hypertension Aug 2022Chronic kidney disease (CKD) and cardiovascular disease (CVD) share major risk factors and mechanistic pathways for progression. Furthermore, either decreased glomerular... (Review)
Review
Chronic kidney disease (CKD) and cardiovascular disease (CVD) share major risk factors and mechanistic pathways for progression. Furthermore, either decreased glomerular filtration rate or increased albuminuria are major risk factors for cardiovascular events. Evidence from previous renal outcome trials in patients with proteinuric CKD showed that angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin-II receptor blockers (ARBs) effectively slow CKD progression, establishing these agents as fundamental CKD pharmacologic treatments. However, in all these trials and subsequent meta-analyses, ACEIs and ARBs did not significantly reduce cardiovascular events or mortality, indicating a high residual risk for CVD progression in individuals with CKD. In contrast to the above, several outcome trials with old and novel mineralocorticoid receptor-antagonists (MRAs) clearly suggest that these agents, apart from nephroprotection, offer important cardioprotection in this population. This article is an overview of previous and recent evidence on the effects of MRAs on cardiovascular outcomes in patients with CKD attempting to highlight a pathway able to improve both cardiovascular and renal prognosis in this population.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Cardiovascular Diseases; Humans; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic
PubMed: 34980878
DOI: 10.1038/s41371-021-00641-1 -
International Journal of Molecular... Nov 2022The automatism of cardiac pacemaker cells, which is tuned, is regulated by the autonomic nervous system (ANS) and multiple endocrine and paracrine factors, including... (Review)
Review
The automatism of cardiac pacemaker cells, which is tuned, is regulated by the autonomic nervous system (ANS) and multiple endocrine and paracrine factors, including cardiovascular peptides. The cardiovascular peptides (CPs) form a group of essential paracrine factors affecting the function of the heart and vessels. They may also be produced in other organs and penetrate to the heart via systemic circulation. The present review draws attention to the role of vasopressin (AVP) and some other cardiovascular peptides (angiotensins, oxytocin, cytokines) in the regulation of the cardiovascular system in health and cardiovascular diseases, especially in post-infarct heart failure, hypertension and cerebrovascular strokes. Vasopressin is synthesized mostly by the neuroendocrine cells of the hypothalamus. There is also evidence that it may be produced in the heart and lungs. The secretion of AVP and other CPs is markedly influenced by changes in blood volume and pressure, as well as by other disturbances, frequently occurring in cardiovascular diseases (hypoxia, pain, stress, inflammation). Myocardial infarction, hypertension and cardiovascular shock are associated with an increased secretion of AVP and altered responsiveness of the cardiovascular system to its action. The majority of experimental studies show that the administration of vasopressin during ventricular fibrillation and cardiac arrest improves resuscitation, however, the clinical studies do not present consisting results. Vasopressin cooperates with the autonomic nervous system (ANS), angiotensins, oxytocin and cytokines in the regulation of the cardiovascular system and its interaction with these regulators is altered during heart failure and hypertension. It is likely that the differences in interactions of AVP with ANS and other CPs have a significant impact on the responsiveness of the cardiovascular system to vasopressin in specific cardiovascular disorders.
Topics: Humans; Cardiovascular Diseases; Oxytocin; Arginine Vasopressin; Cardiovascular System; Vasopressins; Hypertension; Heart Failure; Lung; Angiotensins; Cytokines
PubMed: 36430892
DOI: 10.3390/ijms232214414 -
Scientific Reports Mar 2021This study aimed to focus on the high-value utilization of raw wheat gluten by determining the potent antioxidant peptides and angiotensin I-converting enzyme (ACE)...
This study aimed to focus on the high-value utilization of raw wheat gluten by determining the potent antioxidant peptides and angiotensin I-converting enzyme (ACE) inhibitory peptides from wheat gluten oligopeptides (WOP). WOP were analyzed for in vitro antioxidant activity and inhibition of ACE, and the identification of active peptides was performed by reversed-phase high-performance liquid chromatography and mass spectrometry. Quantitative analysis was performed for highly active peptides. Five potent antioxidant peptides, Leu-Tyr, Pro-Tyr, Tyr-Gln, Ala-Pro-Ser-Tyr and Arg-Gly-Gly-Tyr (6.07 ± 0.38, 7.28 ± 0.29, 11.18 ± 1.02, 5.93 ± 0.20 and 9.04 ± 0.47 mmol 6-hydroxy-2,5,7,8-tetramethylchroman-2-carboxylic acid (Trolox) equivalent/g sample, respectively), and five potent ACE inhibitory peptides, Leu-Tyr, Leu-Val-Ser, Tyr-Gln, Ala-Pro-Ser-Tyr and Arg-Gly-Gly-Tyr (half maximal inhibitory concentration (IC) values = 0.31 ± 0.02, 0.60 ± 0.03, 2.00 ± 0.13, 1.47 ± 0.08 and 1.48 ± 0.11 mmol/L, respectively), were observed. The contents of Leu-Tyr, Pro-Tyr, Tyr-Gln, Ala-Pro-Ser-Tyr, Arg-Gly-Gly-Tyr, and Leu-Val-Ser were 155.04 ± 8.36, 2.08 ± 0.12, 1.95 ± 0.06, 22.70 ± 1.35, 0.25 ± 0.01, and 53.01 ± 2.73 μg/g, respectively, in the WOP. Pro-Tyr, Tyr-Gln, Ala-Pro-Ser-Tyr, Arg-Gly-Gly-Tyr, and Leu-Val-Ser are novel antioxidative/ACE inhibitory peptides that have not been previously reported. The results suggest that WOP could potentially be applied in the food industry as a functional additive.
Topics: Amino Acid Sequence; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Antioxidants; Glutens; Mass Spectrometry; Peptide Fragments; Peptides; Peptidyl-Dipeptidase A; Triticum
PubMed: 33664447
DOI: 10.1038/s41598-021-84820-7 -
European Journal of Heart Failure Mar 2021
Topics: Aldosterone; Angiotensin Receptor Antagonists; Angiotensins; COVID-19; Heart Failure; Hospitalization; Humans; Registries; Renin; Renin-Angiotensin System; SARS-CoV-2
PubMed: 33421242
DOI: 10.1002/ejhf.2098 -
Molecular Biology Reports Feb 2023The renin-angiotensin system is known to maintain blood pressure and body fluids. However, it has been found to consist of at least two major constituents, the classic... (Review)
Review
BACKGROUND
The renin-angiotensin system is known to maintain blood pressure and body fluids. However, it has been found to consist of at least two major constituents, the classic and the alternative pathway, balancing and supporting each other's signalling in a very intricate way. Current research has shown that the renin-angiotensin system is involved in a broad range of biological processes and diseases, such as cancer and infectious diseases.
METHODS AND RESULTS
We conducted a literature review on the interaction of the renin-angiotensin system and prostate cancer and explored the research on the possible impact of the SARS-CoV-2 virus in this context. This review provides an update on contemporary knowledge into the alternative renin-angiotensin system, its role in cancer, specifically prostate cancer, and the implications of the current COVID-19 pandemic on cancer and cancer care.
CONCLUSION
In this work, we aim to demonstrate how shifting the RAS signalling pathway from the classic to the alternative axis seems to be a viable option in supporting treatment of specific cancers and at the same time demonstrating beneficial properties in supportive care. It however seems to be the case that the infection with SARS-CoV-2 and subsequent impairment of the renin-angiotensin-system could exhibit serious deleterious long-term effects even in oncology.
Topics: Humans; Male; Renin-Angiotensin System; COVID-19; Renin; SARS-CoV-2; Pandemics; Angiotensin-Converting Enzyme Inhibitors; Prostatic Neoplasms; Angiotensins; Peptidyl-Dipeptidase A
PubMed: 36478297
DOI: 10.1007/s11033-022-08087-5 -
Seminars in Nephrology May 2023Heart failure (HF), diabetes, and chronic kidney disease (CKD) frequently coexist, with one comorbidity worsening the prognosis of another. β-blockers,... (Review)
Review
Heart failure (HF), diabetes, and chronic kidney disease (CKD) frequently coexist, with one comorbidity worsening the prognosis of another. β-blockers, angiotensin-receptor-neprilysin inhibitors, renin-angiotensin-aldosterone system inhibitors, mineralocorticoid-receptor antagonists, and sodium-glucose cotransporter-2 inhibitors all have been shown to reduce mortality in patients with HF with reduced ejection fraction. However, their uptake in real-world clinical practice remains low, especially among patients who have multiple other comorbidities such as CKD and diabetes. The management of HF in patients with diabetes and CKD can be especially challenging because these patients typically are older, frail, and have multiple other comorbidities, and guideline-directed medical therapy used in HF potentially can affect renal function acutely and chronically. In this article, we discuss the available evidence for each of the foundational HF therapies in patients with diabetes and CKD, emphasizing the current challenges and outlining future directions to optimize the management of HF among these high-risk patients.
Topics: Humans; Stroke Volume; Sodium-Glucose Transporter 2 Inhibitors; Heart Failure; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Diabetes Mellitus; Angiotensins; Angiotensin Receptor Antagonists
PubMed: 37871362
DOI: 10.1016/j.semnephrol.2023.151429