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Physiological Reviews Jan 2018The renin-angiotensin system (RAS) is a key player in the control of the cardiovascular system and hydroelectrolyte balance, with an influence on organs and functions... (Review)
Review
The renin-angiotensin system (RAS) is a key player in the control of the cardiovascular system and hydroelectrolyte balance, with an influence on organs and functions throughout the body. The classical view of this system saw it as a sequence of many enzymatic steps that culminate in the production of a single biologically active metabolite, the octapeptide angiotensin (ANG) II, by the angiotensin converting enzyme (ACE). The past two decades have revealed new functions for some of the intermediate products, beyond their roles as substrates along the classical route. They may be processed in alternative ways by enzymes such as the ACE homolog ACE2. One effect is to establish a second axis through ACE2/ANG-(1-7)/MAS, whose end point is the metabolite ANG-(1-7). ACE2 and other enzymes can form ANG-(1-7) directly or indirectly from either the decapeptide ANG I or from ANG II. In many cases, this second axis appears to counteract or modulate the effects of the classical axis. ANG-(1-7) itself acts on the receptor MAS to influence a range of mechanisms in the heart, kidney, brain, and other tissues. This review highlights the current knowledge about the roles of ANG-(1-7) in physiology and disease, with particular emphasis on the brain.
Topics: Angiotensin I; Angiotensin-Converting Enzyme 2; Animals; Brain; Humans; Peptide Fragments; Peptidyl-Dipeptidase A; Proto-Oncogene Mas; Proto-Oncogene Proteins; Receptors, G-Protein-Coupled; Renin-Angiotensin System; Signal Transduction
PubMed: 29351514
DOI: 10.1152/physrev.00023.2016 -
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 -
Cell Metabolism Jun 2018Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. However, the role of FGF21...
Fibroblast growth factor 21 (FGF21) is a metabolic hormone with pleiotropic effects on glucose and lipid metabolism and insulin sensitivity. However, the role of FGF21 in hypertension remains elusive. Here we show that FGF21 deficiency significantly exacerbates angiotensin II-induced hypertension and vascular dysfunction, whereas such negative effects are reversed by replenishment of FGF21. Mechanistically, FGF21 acts on adipocytes and renal cells to promote induction of angiotensin-converting enzyme 2 (ACE2), which in turn converts angiotensin II to angiotensin-(1-7), then inhibits hypertension and reverses vascular damage. In addition, ACE2 deficiency strikingly abrogates these beneficial effects of FGF21 in mice, including alleviation of angiotensin II-associated hypertension and vascular damage. Otherwise, pharmaceutical inhibition of angiotensin-(1-7) attenuates the protective effect of FGF21 on angiotensin II-induced vascular dysfunction, but not on hypertension. Thus, FGF21 protects against angiotensin II-induced hypertension and vascular impairment by activation of the ACE2/angiotensin-(1-7) axis via fine-tuning the multi-organ crosstalk between liver, adipose tissue, kidney, and blood vessels.
Topics: Adipose Tissue; Angiotensin I; Angiotensin II; Angiotensin-Converting Enzyme 2; Animals; Blood Pressure; Cardiovascular System; Fibroblast Growth Factors; Hypertension; Kidney; Loss of Function Mutation; Mice; Mice, Inbred C57BL; Mice, Knockout; Peptide Fragments; Peptidyl-Dipeptidase A
PubMed: 29706566
DOI: 10.1016/j.cmet.2018.04.002 -
Methods in Molecular Biology (Clifton,... 2017The renin angiotensin system (RAS) is well known for its role in regulating blood pressure (BP). An activated RAS contributes to elevated blood pressure and is evident...
The renin angiotensin system (RAS) is well known for its role in regulating blood pressure (BP). An activated RAS contributes to elevated blood pressure and is evident in both human and animal models of hypertension. Drugs that target the classic vasoconstrictive arm of the RAS (angiotensin II/AT1 receptor signaling) are potent anti-hypertensive agents in clinical setting. However, the newly discovered angiotensin-converting enzyme 2 (ACE2)/angiotensin-(1-7)/Mas receptor axis added new vitality to the hypertension field. Advances in genetic manipulation and the relative low cost made the mouse model as one of the most popular animal models to study hypertension. Since a reliable and accurate method for BP assessment is the key for such experiments, here we provide a protocol for BP measurement in mice using a noninvasive BP system. The CODA noninvasive BP system (a tail-cuff Method, Kent Scientific Corporation) enables blood pressure (BP) measurements in mice. This method uses a specialized volume pressure recording (VPR) sensor, and measures blood volume changes that are placed over the animal's tail. Mice do need to be restrained in specific holders and artificially heated to maintain normal BP.
Topics: Angiotensin I; Animals; Blood Pressure; Blood Pressure Determination; Hypertension; Mice; Peptide Fragments; Renin-Angiotensin System; Software; Tail
PubMed: 28500596
DOI: 10.1007/978-1-4939-7030-8_6 -
Protein and Peptide Letters Nov 2017The renin-angiotensin system (RAS) has two different axes, the classical one with the effector peptide angiotensin II and the new one with the effector peptide... (Review)
Review
The renin-angiotensin system (RAS) has two different axes, the classical one with the effector peptide angiotensin II and the new one with the effector peptide angiotensin (1-7). Both peptides have been shown to be involved in the pathogenesis of diabetes mellitus and its consequences, nephropathy, retinopathy and cardiomyopathy in animal models and patients. In diabetes, angiotensin II acts mostly deleterious and angiotensin (1-7) protective. In this review we summarize the knowledge about the role of the different RAS axes in diabetes mellitus and the use of drugs interfering with the RAS in the therapy of the disease.
Topics: Angiotensin I; Angiotensin II; Animals; Diabetes Mellitus; Humans; Peptide Fragments; Renin-Angiotensin System
PubMed: 28758590
DOI: 10.2174/0929866524666170728144357 -
Metabolism: Clinical and Experimental Jun 2019Nowadays the adipose tissue is recognized as one of the most critical endocrine organs releasing many adipokines that regulate metabolism, inflammation and body... (Review)
Review
Nowadays the adipose tissue is recognized as one of the most critical endocrine organs releasing many adipokines that regulate metabolism, inflammation and body homeostasis. There are several described adipokines, including the renin-angiotensin system (RAS) components that are especially activated in some diseases with increased production of angiotensin II and several pro-inflammatory hormones. On the other hand, RAS also expresses angiotensin-(1-7), which is now recognized as the main peptide on counteracting Ang II effects. New studies have shown that increased activation of ACE2/Ang-(1-7)/MasR arm can revert and prevent local and systemic dysfunctions improving lipid profile and insulin resistance by modulating insulin actions, and reducing inflammation. In this context, the present review shows the interaction and relevance of Ang-(1-7) effects on regulating adipokines, and as one adipokine itself, modulating body homeostasis, with emphasis on its anti-inflammatory properties, especially in the context of metabolic disorders with focus on obesity and type 2 diabetes mellitus pandemic.
Topics: Adipokines; Adipose Tissue; Angiotensin I; Animals; Humans; Inflammation; Peptide Fragments; Proto-Oncogene Mas
PubMed: 30905634
DOI: 10.1016/j.metabol.2019.03.006 -
Methods in Molecular Biology (Clifton,... 2017The renin-angiotensin system (RAS) is a complex circulating and tissue-based system. There are multiple pathways for the formation and degradation of peptides. In order... (Review)
Review
The renin-angiotensin system (RAS) is a complex circulating and tissue-based system. There are multiple pathways for the formation and degradation of peptides. In order to understand the functions of the system, characterization of angiotensin peptides (products and substrates) is important. Radioimmunoassays with the requisite specificity and sensitivity have been developed to allow for the characterization and quantification of circulating and tissue angiotensins. Here, we describe the appropriate methods for collecting the tissue and blood, the extractions steps required to partially purify and remove larger molecular weight-interfering proteins from tissue and plasma, and the radioimmunoassay of three of the peptides of this system (Ang I, Ang II, and Ang-(1-7)), as well as the verification of immunoreactive identity for Ang II and Ang-(1-7) by combined high-performance liquid chromatography-RIA analysis.
Topics: Angiotensin I; Angiotensin II; Animals; Chromatography, High Pressure Liquid; Humans; Peptide Fragments; Radioimmunoassay; Renin-Angiotensin System
PubMed: 28116709
DOI: 10.1007/978-1-4939-6625-7_7 -
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