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Journal of Molecular Medicine (Berlin,... Jun 2008For many years, prorenin has been considered to be nothing more than the inactive precursor of renin. Yet, its elevated levels in diabetic subjects with microvascular... (Review)
Review
For many years, prorenin has been considered to be nothing more than the inactive precursor of renin. Yet, its elevated levels in diabetic subjects with microvascular complications and its extrarenal production at various sites in the body suggest otherwise. This review discusses the origin, regulation, and enzymatic activity of prorenin, its role during renin inhibition, and the angiotensin-dependent and angiotensin-independent consequences of its binding to the recently discovered (pro)renin receptor. The review ends with the concept that prorenin rather than renin determines tissue angiotensin generation.
Topics: Angiotensins; Animals; Humans; Receptors, Cell Surface; Renin; Prorenin Receptor
PubMed: 18322669
DOI: 10.1007/s00109-008-0318-2 -
Physiological Research 2015Bone is a target tissue for hormones, such as the sex steroids, parathormon, vitamin D, calcitonin, glucocorticoids, and thyroid hormones. In the last decade, other... (Review)
Review
Bone is a target tissue for hormones, such as the sex steroids, parathormon, vitamin D, calcitonin, glucocorticoids, and thyroid hormones. In the last decade, other "non-classic" hormones that modulate the bone tissue have been identified. While incretins (GIP and GLP-1) inhibit bone remodeling, angiotensin acts to promote remodeling. Bone morphogenetic protein (BMP) has also been found to have anabolic effects on the skeleton by activating bone formation during embryonic development, as well as in the postnatal period of life. Bone has also been identified as an endocrine tissue that produces a number of hormones, that bind to and modulate extra-skeletal receptors. Osteocalcin occupies a central position in this context. It can increase insulin secretion, insulin sensitivity and regulate metabolism of fatty acids. Moreover, osteocalcin also influences phosphate metabolism via osteocyte-derived FGF23 (which targets the kidneys and parathyroid glands to control phosphate reabsorption and metabolism of vitamin D). Finally, osteocalcin stimulates testosterone synthesis in Leydig cells and thus may play some role in male fertility. Further studies are necessary to confirm clinically important roles for skeletal tissue in systemic regulations.
Topics: Angiotensins; Animals; Bone Morphogenetic Proteins; Bone and Bones; Endocrine System; Fibroblast Growth Factor-23; Hormones; Humans; Incretins; Models, Biological; Osteocalcin
PubMed: 25470522
DOI: 10.33549/physiolres.932900 -
Journal of the... Dec 2014Apart from the well-documented role of the renin-angiotensin-aldosterone system (RAAS) in regulating the blood pressure and other related parameters, its role in... (Review)
Review
Apart from the well-documented role of the renin-angiotensin-aldosterone system (RAAS) in regulating the blood pressure and other related parameters, its role in modulating different physiological/pathological functions, including pain, has also been described. Like its dual role in regulating stress-related anxiety and cognitive functions, its dual role has also been documented in pain modulation in different disease states. Drugs blocking the RAAS activation, viz., renin inhibitors, angiotensin converting enzyme (ACE) inhibitors, AT(1) receptor antagonists and aldosterone antagonists, have been shown to produce beneficial effects in migraine and neuropathic and nociceptive pain. Their beneficial effects have been mainly attributed to inhibition of the inflammatory cascade of reactions by inhibiting the generation of key cytokines, including tumor necrosis factor (TNF)-α. On the contrary, clinical as well as preclinical studies have also shown the pain-inducing actions of renin-angiotensin system (RAS) blocking drugs. Furthermore, the pain-relieving actions of angiotensin II (AngII) and pain-inducing actions of AT(1) blockers have also been described. The pain-inducing actions of ACE inhibitors have been mainly attributed to interference with metabolism of bradykinin and substance P, while the analgesic actions of AngII have been mainly related to activation of brain localized AT(2) receptors and release of endogenous opioids. The present review describes the dual role of the RAAS in different states of pain.
Topics: Angiotensins; Humans; Models, Biological; Pain; Renin-Angiotensin System
PubMed: 25503939
DOI: 10.1177/1470320313503694 -
Journal of Molecular and Cellular... Jan 2020Chronically elevated angiotensin II is a widely-established contributor to hypertension and heart failure via its action on the kidneys and vasculature. It also augments...
Chronically elevated angiotensin II is a widely-established contributor to hypertension and heart failure via its action on the kidneys and vasculature. It also augments the activity of peripheral sympathetic nerves through activation of presynaptic angiotensin II receptors, thus contributing to sympathetic over-activity. Although some cells can synthesise angiotensin II locally, it is not known if this machinery is present in neurons closely coupled to the heart. Using a combination of RNA sequencing and quantitative real-time polymerase chain reaction, we demonstrate evidence for a renin-angiotensin synthesis pathway within human and rat sympathetic stellate ganglia, where significant alterations were observed in the spontaneously hypertensive rat stellate ganglia compared with Wistar stellates. We also used Förster Resonance Energy Transfer to demonstrate that administration of angiotensin II and angiotensin 1-7 peptides significantly elevate cyclic guanosine monophosphate in the rat stellate ganglia. Whether the release of angiotensin peptides from the sympathetic stellate ganglia alters neurotransmission and/or exacerbates cardiac dysfunction in states associated with sympathetic over activity remains to be established.
Topics: Adult; Aged; Angiotensins; Animals; Cyclic GMP; Female; Gene Expression Regulation; Humans; Male; Middle Aged; Models, Biological; Nucleotides, Cyclic; Principal Component Analysis; RNA, Messenger; Rats, Inbred SHR; Rats, Wistar; Renin; Stellate Ganglion; Sympathetic Nervous System; Transcriptome; Young Adult
PubMed: 31836539
DOI: 10.1016/j.yjmcc.2019.11.157 -
International Journal of Molecular... Jul 2016The renin-angiotensin system (RAS) plays a crucial role in cardiovascular regulations and its modulation is a challenging target for the vast majority of... (Review)
Review
The renin-angiotensin system (RAS) plays a crucial role in cardiovascular regulations and its modulation is a challenging target for the vast majority of cardioprotective strategies. However, many biological effects of these drugs cannot be explained by the known mode of action. Our comprehension of the RAS is thus far from complete. The RAS represents an ingenious system of "checks and balances". It incorporates vasoconstrictive, pro-proliferative, and pro-inflammatory compounds on one hand and molecules with opposing action on the other hand. The list of these molecules is still not definitive because new biological properties can be achieved by minor alteration of the molecular structure. The angiotensin A/alamandine-MrgD cascade associates the deleterious and protective branches of the RAS. Its identification provided a novel clue to the understanding of the RAS. Angiotensin A (Ang A) is positioned at the "crossroad" in this system since it either elicits direct vasoconstrictive and pro-proliferative actions or it is further metabolized to alamandine, triggering opposing effects. Alamandine, the central molecule of this cascade, can be generated both from the "deleterious" Ang A as well as from the "protective" angiotensin 1-7. This pathway modulates peripheral and central blood pressure regulation and cardiovascular remodeling. Further research will elucidate its interactions in cardiovascular pathophysiology and its possible therapeutic implications.
Topics: Angiotensins; Cardiovascular Diseases; Humans; Oligopeptides; Receptors, G-Protein-Coupled
PubMed: 27447621
DOI: 10.3390/ijms17071098 -
Heart (British Cardiac Society) Nov 1996The beneficial effects of angiotensin converting enzyme (ACE) inhibitors in heart failure appear to be independent, at least in part, of their effect on blood pressure.... (Review)
Review
The beneficial effects of angiotensin converting enzyme (ACE) inhibitors in heart failure appear to be independent, at least in part, of their effect on blood pressure. The existence of a local cardiac renin angiotensin system is often suggested as an explanation. It has been known for some time that a substantial proportion of arterially delivered angiotensin I is converted to angiotensin II by ACE of the coronary vascular endothelium. The levels of angiotensin II in cardiac tissue are several times the levels of angiotensin II in circulating blood. Recent evidence suggests that most of the angiotensin II in the heart is not derived from angiotensin I in the circulation, and that most of the angiotensin I in cardiac tissue is generated in the tissue itself. On the other hand, renin mRNA levels are very low or undetectable in the normal heart. In addition, studies on the effects of bilateral nephrectomy on the cardiac tissue levels of renin, angiotensin I, and angiotensin II in pigs have indicated that cardiac renin originates from the kidney and that cardiac generation of angiotensin I and angiotensin II depends on renin from the kidney. Intracardiac synthesis of renin may occur under pathological conditions and during fetal development. The fact that angiotensins are generated by the heart raises the possibility of local mechanisms to regulate the concentrations of these peptides at certain tissue sites. For example, preliminary evidence suggests that binding of renin to cardiac membranes is a mechanism by which renin is taken up by the heart. A specific renin binding protein has been identified in cardiac tissue. Cardiac ACE levels may also influence local angiotensin II formation and are, in part, determined by the so called insertion/deletion ACE gene polymorphism. More detailed knowledge on the site of angiotensin generation and on its regulation will improve our understanding of the role of the renin-angiotensin system in cardiac function, hypertrophy, and postinfarction remodelling.
Topics: Angiotensin I; Angiotensin II; Animals; Humans; Kidney; Myocardium; Peptidyl-Dipeptidase A; Rats; Renin; Renin-Angiotensin System; Sheep; Swine; Transcription, Genetic
PubMed: 8983664
DOI: 10.1136/hrt.76.3_suppl_3.28 -
American Journal of Hypertension Dec 2015The renin-angiotensin system is a complex regulatory hormonal network with a main biological peptide and therapeutic target, angiotensin (Ang) II (1-8). There are other...
BACKGROUND
The renin-angiotensin system is a complex regulatory hormonal network with a main biological peptide and therapeutic target, angiotensin (Ang) II (1-8). There are other potentially important Ang peptides that have not been well evaluated.
METHODS
Liquid chromatography-tandem mass spectrometry (LC-MS/MS) was used for concurrent evaluation of multiple Angs downstream of Ang I (1-10) and Ang II (1-8) in kidney and plasma from wild-type (WT) mice. Angiotensin converting enzyme 2 knockout (ACE2KO) was also used as a way to examine the Angs profile in the absence of ACE2, an enzyme that cleaves both Ang I (1-10) and Ang II (1-8).
RESULTS
In plasma from both WT and ACE2KO, levels of Ang I (1-10), Ang III (2-8), and Ang (2-10) were the highest of all the renin-angiotensin system (RAS) peptides. The latter two peptides are products of aminopeptidase A cleavage of Ang II (1-8) and Ang I (1-10), respectively. In contrast, plasma levels of Ang II (1-8), and Ang (1-7), the product of Ang II (1-8) cleavage by ACE2, were low. In kidney from both WT and ACE2KO, Ang II (1-8) levels were high as compared to plasma levels. In the ACE2KO mice, a significant increase in either Ang II (1-8) or a decrease in Ang (1-7) was not observed in plasma or in the kidney.
CONCLUSION
RAS-focused peptidomic approach revealed major differences in Ang peptides between mouse plasma and kidney. These Ang peptide profiles show the dominance of the aminopeptidase A/Ang (2-10) and aminopeptidase A/Ang III (2-8) pathways in the metabolism of Ang I (1-10) and Ang II (1-8) over the ACE2/Ang (1-7) axis. Ang III (2-8) and other peptides formed from aminopeptidase A cleavage may be important therapeutic RAS targets.
Topics: Angiotensin-Converting Enzyme 2; Angiotensins; Animals; Female; Glutamyl Aminopeptidase; Kidney; Male; Mice, Inbred C57BL; Mice, Knockout; Peptidyl-Dipeptidase A; Renin-Angiotensin System
PubMed: 25968123
DOI: 10.1093/ajh/hpv054 -
Journal of the... 2022The SARS-CoV-2 virus is spreading around the world, and its clinical manifestation COVID-19 is challenging medical, economic, and social systems. With more and more... (Review)
Review
The SARS-CoV-2 virus is spreading around the world, and its clinical manifestation COVID-19 is challenging medical, economic, and social systems. With more and more scientific and social media reports on the COVID-19 pandemic appearing, differences in geographical presentations and clinical management occur. Since ACE2 (angiotensin-converting enzyme 2) is the gatekeeper receptor for the SARS-CoV-2 virus in the upper bronchial system, we here focus on the central role of the renin-angiotensin aldosterone system (RAAS) in the SARS-CoV-2 virus infection, the role of pharmacological RAAS inhibitors, and specific genetic aspects, i.e., single nucleotide polymorphisms (SNP) for the clinical outcome of COVID-19. We aimed to bring together clinical, epidemiological, molecular, and pathophysiological and pharmacological data/observations on cardiovascular aspects in the actual SARS-CoV-2 virus pandemic. In detail, we will report controversies about the Yin-Yan between ACE2 and ACE1 and potential implications for the treatment of hypertension, coronary artery disease, and heart failure. Here, we summarize the encouraging and dynamic global effort of multiple biomedical disciplines resulted in astonishing fight against COVID-19 targeting the renin-angiotensin-aldosterone system, yet the race for ACE just begun.
Topics: Angiotensin-Converting Enzyme 2; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Humans; Pandemics; Peptidyl-Dipeptidase A; SARS-CoV-2; COVID-19 Drug Treatment
PubMed: 35685188
DOI: 10.1155/2022/2549063 -
American Journal of Physiology.... Sep 2014The kidney is a key target organ for bioactive components of the renin-angiotensin system (RAS); however, various renal cells such as the tubular epithelium contain an... (Review)
Review
The kidney is a key target organ for bioactive components of the renin-angiotensin system (RAS); however, various renal cells such as the tubular epithelium contain an intrinsic RAS. The renal RAS can be functionally divided into ANG II-AT1 receptor and ANG-(1-7)-AT7/Mas receptor arms that functionally oppose one another. The current review considers both extracellular and intracellular pathways that potentially govern the formation and metabolism of angiotensin peptides within the renal proximal tubules.
Topics: Angiotensin I; Angiotensins; Animals; Humans; Kidney Tubules, Proximal; Peptide Fragments; Receptor, Angiotensin, Type 1; Renin-Angiotensin System
PubMed: 24944244
DOI: 10.1152/ajpregu.00177.2014 -
Basic & Clinical Pharmacology &... Sep 2021Inflammatory bowel diseases (IBDs) are chronic disorders of the gastrointestinal tract, which manifest in recurring gastrointestinal inflammation. The current treatment... (Review)
Review
Inflammatory bowel diseases (IBDs) are chronic disorders of the gastrointestinal tract, which manifest in recurring gastrointestinal inflammation. The current treatment options of IBD are not curative and are lacking in aspects like prevention of fibrosis. New treatment options are needed to fulfil the unmet needs and provide alternatives to drugs with resistances and side effects. Drugs targeting the renin-angiotensin system (RAS), besides being antihypertensive, also possess anti-inflammatory and antifibrotic properties and could offer an inexpensive alternative to control inflammation and fibrosis in the gut. RAS inhibitors have been effective in preventing and alleviating colitis in preclinical studies, but available human data are still sparse. This review outlines the pathophysiological functions of RAS in the gut and summarizes preclinical studies utilizing pharmacological RAS inhibitors in the treatment of experimental colitis. We discuss the alterations in intestinal RAS and the available evidence of the benefits of RAS inhibitors for IBD patients. Retrospective studies comparing IBD patients using ACE inhibitors or angiotensin II receptor blockers have provided optimistic results regarding a milder disease course and fewer hospitalizations and corticosteroid use in patients using RAS inhibitors. Prospective studies are needed to evaluate the effectiveness of these promising medications in the treatment of IBD.
Topics: Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Angiotensins; Animals; Antihypertensive Agents; Colitis; Drug Evaluation, Preclinical; Fibrosis; Humans; Hypertension; Inflammation; Inflammatory Bowel Diseases; Mice; Models, Animal; Renin-Angiotensin System; Retrospective Studies
PubMed: 34128327
DOI: 10.1111/bcpt.13624