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The Surgical Clinics of North America Aug 2023Renovascular hypertension (RVH) is a secondary form of high blood pressure resulting from impaired blood flow to the kidneys with subsequent activation of the... (Review)
Review
Renovascular hypertension (RVH) is a secondary form of high blood pressure resulting from impaired blood flow to the kidneys with subsequent activation of the renin-angiotensin-aldosterone system. Often, this occurs due to abnormally small, narrowed, or blocked blood vessels supplying one or both kidneys (ie: renal artery occlusive disease) and is correctable. Juxtaglomerular cells release renin in response to decreased pressure, which in turn catalyzes the cleavage of circulating angiotensinogen synthesized by the liver to the decapeptide angiotensin I. Angiotensin-converting enzyme then cleaves angiotensin I to form the octapeptide angiotensin II, a potent vasopressor and the primary effector of renin-induced hypertension. The effects of angiotensin II are mediated by signaling downstream of its receptors. Angiotensin receptor type 1 is a G-protein-coupled receptor that activates vasoconstrictor and mitogenic signaling pathways resulting in peripheral arteriolar vasoconstriction and increased renal tubular reabsorption of sodium and water which promotes intravascular volume expansion. Angiotensin II stimulates the adrenal cortical release of aldosterone, which promotes renal tubular sodium reabsorption, resulting in volume expansion. Angiotensin II acts on glial cells and regions of the brain responsible for blood pressure regulation increasing renal sympathetic activation. Angiotensin II simulates the release of vasopressin from the pituitary which stimulates thirst and water reabsorption from the kidney to expand the intravascular volume and cause peripheral vasoconstriction (increased sympathetic tone). All of these mechanisms coalesce to increase arterial pressure by way of arteriolar constriction, enhanced cardiac output, and the retention of sodium and water.
Topics: Humans; Hypertension, Renovascular; Renin; Angiotensin II; Angiotensin I; Hypertension; Blood Pressure; Sodium
PubMed: 37455034
DOI: 10.1016/j.suc.2023.05.007 -
Hypertension (Dallas, Tex. : 1979) May 2024The renin-angiotensin system is the most important peptide hormone system in the regulation of cardiovascular homeostasis. Its classical arm consists of the enzymes,... (Review)
Review
The renin-angiotensin system is the most important peptide hormone system in the regulation of cardiovascular homeostasis. Its classical arm consists of the enzymes, renin, and angiotensin-converting enzyme, generating angiotensin II from angiotensinogen, which activates its AT receptor, thereby increasing blood pressure, retaining salt and water, and inducing cardiovascular hypertrophy and fibrosis. However, angiotensin II can also activate a second receptor, the AT receptor. Moreover, the removal of the C-terminal phenylalanine from angiotensin II by ACE2 (angiotensin-converting enzyme 2) yields angiotensin-(1-7), and this peptide interacts with its receptor Mas. When the aminoterminal Asp of angiotensin-(1-7) is decarboxylated, alamandine is generated, which activates the Mas-related G-protein-coupled receptor D, MrgD (Mas-related G-protein-coupled receptor type D). Since Mas, MrgD, and the AT receptor have opposing effects to the classical AT receptor, they and the enzymes and peptides activating them are called the alternative or protective arm of the renin-angiotensin system. This review will cover the historical aspects and the current standing of this recent addition to the biology of the renin-angiotensin system.
Topics: Angiotensin I; Angiotensin II; Peptide Fragments; Peptides; Peptidyl-Dipeptidase A; Receptors, G-Protein-Coupled; Renin; Renin-Angiotensin System; Humans
PubMed: 38362781
DOI: 10.1161/HYPERTENSIONAHA.123.21364 -
Biochemical Pharmacology Sep 2022Angiotensin-(1-9) [Ang-(1-9)] is a peptide of the non-canonical renin-angiotensin system (RAS) synthesized from angiotensin I by the monopeptidase angiotensin-converting... (Review)
Review
Angiotensin-(1-9) [Ang-(1-9)] is a peptide of the non-canonical renin-angiotensin system (RAS) synthesized from angiotensin I by the monopeptidase angiotensin-converting enzyme type 2 (ACE2). Using osmotic minipumps, infusion of Ang-(1-9) consistently reduces blood pressure in several rat hypertension models. In these animals, hypertension-induced end-organ damage is also decreased. Several pieces of evidence suggest that Ang-(1-9) is the endogenous ligand that binds and activates the type-2 angiotensin II receptor (AT2R). Activation of AT2R triggers different tissue-specific signaling pathways. This phenomenon could be explained by the ability of AT2R to form different heterodimers with other G protein-coupled receptors. Because of the antihypertensive and protective effects of AT2R activation by Ang-(1-9), associated with a short half-life of RAS peptides, several synthetic AT2R agonists have been synthesized and assayed. Some of them, particularly CGP42112, C21 and novokinin, have demonstrated antihypertensive properties. Only two synthetic AT2R agonists, C21 and LP2-3, have been tested in clinical trials, but none of them like an antihypertensive. Therefore, Ang-(1-9) is a promising antihypertensive drug that reduces hypertension-induced end-organ damage. However, further research is required to translate this finding successfully to the clinic.
Topics: Angiotensin I; Angiotensin II; Animals; Antihypertensive Agents; Hypertension; Imidazoles; Peptidyl-Dipeptidase A; Rats; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Sulfonamides; Thiophenes
PubMed: 35870482
DOI: 10.1016/j.bcp.2022.115183 -
Molecular and Cellular Endocrinology Jun 2021The most classical view of the renin-angiotensin system (RAS) emphasizes its role as an endocrine regulator of sodium balance and blood pressure. However, it has long... (Review)
Review
The most classical view of the renin-angiotensin system (RAS) emphasizes its role as an endocrine regulator of sodium balance and blood pressure. However, it has long become clear that the RAS has pleiotropic actions that contribute to organ damage, including modulation of inflammation. Angiotensin II (Ang II) activates angiotensin type 1 receptors (AT1R) to promote an inflammatory response and organ damage. This represents the pathophysiological basis for the successful use of RAS blockers to prevent and treat kidney and heart disease. However, other RAS components could have a built-in capacity to brake proinflammatory responses. Angiotensin type 2 receptor (AT2R) activation can oppose AT1R actions, such as vasodilatation, but its involvement in modulation of inflammation has not been conclusively proven. Angiotensin-converting enzyme 2 (ACE2) can process Ang II to generate angiotensin-(1-7) (Ang-(1-7)), that activates the Mas receptor to exert predominantly anti-inflammatory responses depending on the context. We now review recent advances in the understanding of the interaction of the RAS with inflammation. Specific topics in which novel information became available recently include intracellular angiotensin receptors; AT1R posttranslational modifications by tissue transglutaminase (TG2) and anti-AT1R autoimmunity; RAS modulation of lymphoid vessels and T lymphocyte responses, especially of Th17 and Treg responses; interactions with toll-like receptors (TLRs), programmed necrosis, and regulation of epigenetic modulators (e.g. microRNAs and bromodomain and extraterminal domain (BET) proteins). We additionally discuss an often overlooked effect of the RAS on inflammation which is the downregulation of anti-inflammatory factors such as klotho, peroxisome proliferator-activated receptor γ co-activator 1α (PGC-1α), transient receptor potential ankyrin 1 (TRPA1), SNF-related serine/threonine-protein kinase (SNRK), serine/threonine-protein phosphatase 6 catalytic subunit (Ppp6C) and n-acetyl-seryl-aspartyl-lysyl-proline (Ac-SDKP). Both transcription factors, such as nuclear factor κB (NF-κB), and epigenetic regulators, such as miRNAs are involved in downmodulation of anti-inflammatory responses. A detailed analysis of pathways and targets for downmodulation of anti-inflammatory responses constitutes a novel frontier in RAS research.
Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Autoimmunity; Blood Pressure; Gene Expression Regulation; Humans; Inflammation; Kidney; Klotho Proteins; Peptide Fragments; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Renin-Angiotensin System; Signal Transduction; T-Lymphocytes; Water-Electrolyte Balance
PubMed: 33798633
DOI: 10.1016/j.mce.2021.111254 -
Molecular and Cellular Endocrinology Jun 2021
Topics: Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Angiotensinogen; Animals; Blood Pressure; Chymases; Diabetic Nephropathies; Gene Expression Regulation; Humans; Hypertension; Kidney; Peptide Fragments; Renin-Angiotensin System; Signal Transduction; Water-Electrolyte Balance
PubMed: 33819521
DOI: 10.1016/j.mce.2021.111268 -
American Journal of Hypertension Nov 2019Despite decades of research and numerous treatment approaches, hypertension and cardiovascular disease remain leading global public health problems. A major contributor... (Review)
Review
Despite decades of research and numerous treatment approaches, hypertension and cardiovascular disease remain leading global public health problems. A major contributor to regulation of blood pressure, and the development of hypertension, is the renin-angiotensin system. Of particular concern, uncontrolled activation of angiotensin II contributes to hypertension and associated cardiovascular risk, with antihypertensive therapies currently available to block the formation and deleterious actions of this hormone. More recently, angiotensin-(1-7) has emerged as a biologically active intermediate of the vasodilatory arm of the renin-angiotensin system. This hormone antagonizes angiotensin II actions as well as offers antihypertensive, antihypertrophic, antiatherogenic, antiarrhythmogenic, antifibrotic and antithrombotic properties. Angiotensin-(1-7) elicits beneficial cardiovascular actions through mas G protein-coupled receptors, which are found in numerous tissues pivotal to control of blood pressure including the brain, heart, kidneys, and vasculature. Despite accumulating evidence for favorable effects of angiotensin-(1-7) in animal models, there is a paucity of clinical studies and pharmacokinetic limitations, thus limiting the development of therapeutic agents to better understand cardiovascular actions of this vasodilatory peptide hormone in humans. This review highlights current knowledge on the role of angiotensin-(1-7) in cardiovascular control, with an emphasis on significant animal, human, and therapeutic research efforts.
Topics: Angiotensin I; Animals; Antihypertensive Agents; Blood Pressure; Cardiovascular System; Humans; Hypertension; Peptide Fragments; Renin-Angiotensin System; Signal Transduction; Vasodilator Agents
PubMed: 31602467
DOI: 10.1093/ajh/hpz146 -
Peptides Jun 2022Angiotensin converting enzyme (ACE) is well known for its role producing the vasoconstrictor angiotensin II and ACE inhibitors are commonly used for treating...
Angiotensin converting enzyme (ACE) is well known for its role producing the vasoconstrictor angiotensin II and ACE inhibitors are commonly used for treating hypertension and cardiovascular disease. However, ACE has many different substrates besides angiotensin I and plays a role in many different physiologic processes. Here, we discuss the role of ACE in the immune response. Several studies in mice indicate that increased expression of ACE by macrophages or neutrophils enhances the ability of these cells to respond to immune challenges such as infection, neoplasm, Alzheimer's disease, and atherosclerosis. Increased expression of ACE induces increased oxidative metabolism with an increase in cell content of ATP. In contrast, ACE inhibitors have the opposite effect, and in both humans and mice, administration of ACE inhibitors reduces the ability of neutrophils to kill bacteria. Understanding how ACE affects the immune response may provide a means to increase immunity in a variety of chronic conditions now not treated through immune manipulation.
Topics: Angiotensin I; Angiotensin-Converting Enzyme Inhibitors; Animals; Hypertension; Macrophages; Mice; Peptidyl-Dipeptidase A
PubMed: 35182689
DOI: 10.1016/j.peptides.2022.170769 -
Cells Jul 2020The newly emergent novel coronavirus disease 2019 (COVID-19) outbreak, which is caused by SARS-CoV-2 virus, has posed a serious threat to global public health and caused... (Review)
Review
The newly emergent novel coronavirus disease 2019 (COVID-19) outbreak, which is caused by SARS-CoV-2 virus, has posed a serious threat to global public health and caused worldwide social and economic breakdown. Angiotensin-converting enzyme 2 (ACE2) is expressed in human vascular endothelium, respiratory epithelium, and other cell types, and is thought to be a primary mechanism of SARS-CoV-2 entry and infection. In physiological condition, ACE2 via its carboxypeptidase activity generates angiotensin fragments (Ang 1-9 and Ang 1-7), and plays an essential role in the renin-angiotensin system (RAS), which is a critical regulator of cardiovascular homeostasis. SARS-CoV-2 via its surface spike glycoprotein interacts with ACE2 and invades the host cells. Once inside the host cells, SARS-CoV-2 induces acute respiratory distress syndrome (ARDS), stimulates immune response (i.e., cytokine storm) and vascular damage. SARS-CoV-2 induced endothelial cell injury could exacerbate endothelial dysfunction, which is a hallmark of aging, hypertension, and obesity, leading to further complications. The pathophysiology of endothelial dysfunction and injury offers insights into COVID-19 associated mortality. Here we reviewed the molecular basis of SARS-CoV-2 infection, the roles of ACE2, RAS signaling, and a possible link between the pre-existing endothelial dysfunction and SARS-CoV-2 induced endothelial injury in COVID-19 associated mortality. We also surveyed the roles of cell adhesion molecules (CAMs), including CD209L/L-SIGN and CD209/DC-SIGN in SARS-CoV-2 infection and other related viruses. Understanding the molecular mechanisms of infection, the vascular damage caused by SARS-CoV-2 and pathways involved in the regulation of endothelial dysfunction could lead to new therapeutic strategies against COVID-19.
Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Betacoronavirus; COVID-19; Cell Adhesion Molecules; Coronavirus Infections; Endothelium, Vascular; Host Microbial Interactions; Humans; Pandemics; Peptidyl-Dipeptidase A; Pneumonia, Viral; Renin-Angiotensin System; SARS-CoV-2; Signal Transduction
PubMed: 32660065
DOI: 10.3390/cells9071652