Renin-Angiotensin System in Diseases

A special issue of Biomolecules (ISSN 2218-273X). This special issue belongs to the section "Cellular Biochemistry".

Deadline for manuscript submissions: closed (30 November 2022) | Viewed by 13723

Special Issue Editors

Laboratory of Cardiovascular Pharmacology, Department of Biopharmaceutical Sciences, Kobe Gakuin University, Minatojima 1-1-3, Chuo-ku, Kobe 650-8586, Japan
Interests: angiotensin; angiotensin type 1 receptor; angiotensin type 2 receptor; myosin light chin phosphatase; hypertension; bradykinin; eNOS
Special Issues, Collections and Topics in MDPI journals
Department of Medicine, University of Padova, Padova, Italy
Interests: renin angiotensin aldosterone system; endocrine hypertensions; inborn errors of metabolism; parathyroid hormone
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

The renin–angiotensin–aldosterone system is a homeostatic endocrine system which is of critical importance to the regulation of blood pressure and maintenance of fluid and electrolyte balance. Angiotensin II (Ang II), the most active component of the renin–angiotensin system, is a multifunctional hormone that plays an important role in cardiovascular physiology and pathology. In addition, we know well that angiotensin, angiotensin-related peptides such as angiotensin III, angiotensin IV, angiotensin 1-7, and angiotensin 1-9, and factors (angiotensin receptor, renin, renin receptor, and angiotensin-converting enzyme) of the renin–angiotensin system have various physiological activities.

These factors have been reported to be involved in the development of hypertension, heart disease, kidney disease, inflammation, and diabetes. New findings have been reported on how these factors are involved in disease progression. Furthermore, COVID-19, which has been a threat to the world since the end of last year, accepts angiotensin-converting enzyme 2 as a receptor. Therefore, it has been reported that coronavirus infection causes abnormalities in the blood coagulation system by damaging vascular endothelial cells, resulting in damage to various organs.

The purpose of this Special Issue of Biomolecules is to highlight the relationship between the renin–angiotensin system and pathophysiology, and to introduce their involvement in the onset of diseases, such as hypertension, heart disease, kidney disease, inflammation, diabetes, and coronavirus infection, and their application to elucidation of treatment.

Prof. Dr. Katsutoshi Yayama
Dr. Livia Lenzini
Guest Editor

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Keywords

  • renin
  • angiotensin
  • angiotensin-converting enzyme
  • angiotensin receptor
  • MAS receptor
  • alamandine
  • aminopeptidase

Published Papers (6 papers)

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Research

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17 pages, 4438 KiB  
Article
(Pro)Renin Receptor Antagonism Attenuates High-Fat-Diet–Induced Hepatic Steatosis
by Ariana Julia B. Gayban, Lucas A. C. Souza, Silvana G. Cooper, Erick Regalado, Robert Kleemann and Yumei Feng Earley
Biomolecules 2023, 13(1), 142; https://0-doi-org.brum.beds.ac.uk/10.3390/biom13010142 - 10 Jan 2023
Cited by 2 | Viewed by 1707
Abstract
Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver damage directly related to diabetes, obesity, and metabolic syndrome. The (pro)renin receptor (PRR) has recently been demonstrated to play a role in glucose and lipid metabolism. Here, we test the hypothesis that the [...] Read more.
Non-alcoholic fatty liver disease (NAFLD) comprises a spectrum of liver damage directly related to diabetes, obesity, and metabolic syndrome. The (pro)renin receptor (PRR) has recently been demonstrated to play a role in glucose and lipid metabolism. Here, we test the hypothesis that the PRR regulates the development of diet-induced hepatic steatosis and fibrosis. C57Bl/6J mice were fed a high-fat diet (HFD) or normal-fat diet (NFD) with matching calories for 6 weeks. An 8-week methionine choline-deficient (MCD) diet was used to induce fibrosis. Two weeks following diet treatment, mice were implanted with a subcutaneous osmotic pump delivering either the peptide PRR antagonist, PRO20, or scrambled peptide for 4 or 6 weeks. Mice fed a 6-week HFD exhibited increased liver lipid accumulation and liver triglyceride content compared with NFD-fed mice. Importantly, PRO20 treatment reduced hepatic lipid accumulation in HFD-fed mice without affecting body weight or blood glucose. Furthermore, PRR antagonism attenuated HFD-induced steatosis, particularly microvesicular steatosis. In the MCD diet model, the percentage of collagen area was reduced in PRO20-treated compared with control mice. PRO20 treatment also significantly decreased levels of liver alanine aminotransferase, an indicator of liver damage, in MCD-fed mice compared with controls. Mechanistically, we found that PRR antagonism prevented HFD-induced increases in PPARγ and glycerol-3-phosphate acyltransferase 3 expression in the liver. Taken together, our findings establish the involvement of the PRR in liver triglyceride synthesis and suggest the therapeutic potential of PRR antagonism for the treatment of liver steatosis and fibrosis in NAFLD. Full article
(This article belongs to the Special Issue Renin-Angiotensin System in Diseases)
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20 pages, 5134 KiB  
Article
Renin-a in the Subfornical Organ Plays a Critical Role in the Maintenance of Salt-Sensitive Hypertension
by Silvana G. Cooper, Lucas A. C. Souza, Caleb J. Worker, Ariana Julia B. Gayban, Sophie Buller, Ryosuke Satou and Yumei Feng Earley
Biomolecules 2022, 12(9), 1169; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12091169 - 24 Aug 2022
Cited by 1 | Viewed by 1713
Abstract
The brain renin-angiotensin system plays important roles in blood pressure and cardiovascular regulation. There are two isoforms of prorenin in the brain: the classic secreted form (prorenin/sREN) encoded by renin-a, and an intracellular form (icREN) encoded by renin-b. Emerging evidence indicates the importance [...] Read more.
The brain renin-angiotensin system plays important roles in blood pressure and cardiovascular regulation. There are two isoforms of prorenin in the brain: the classic secreted form (prorenin/sREN) encoded by renin-a, and an intracellular form (icREN) encoded by renin-b. Emerging evidence indicates the importance of renin-b in cardiovascular and metabolic regulation. However, the role of endogenous brain prorenin in the development of salt-sensitive hypertension remains undefined. In this study, we test the hypothesis that renin-a produced locally in the brain contributes to the pathogenesis of hypertension. Using RNAscope, we report for the first time that renin mRNA is expressed in several regions of the brain, including the subfornical organ (SFO), the paraventricular nucleus of the hypothalamus (PVN), and the brainstem, where it is found in glutamatergic, GABAergic, cholinergic, and tyrosine hydroxylase-positive neurons. Notably, we found that renin mRNA was significantly elevated in the SFO and PVN in a mouse model of DOCA-salt–induced hypertension. To examine the functional importance of renin-a in the SFO, we selectively ablated renin-a in the SFO in renin-a–floxed mice using a Cre-lox strategy. Importantly, renin-a ablation in the SFO attenuated the maintenance of DOCA-salt–induced hypertension and improved autonomic function without affecting fluid or sodium intake. Molecularly, ablation of renin-a prevented the DOCA-salt–induced elevation in NADPH oxidase 2 (NOX2) in the SFO without affecting NOX4 or angiotensin II type 1 and 2 receptors. Collectively, our findings demonstrate that endogenous renin-a within the SFO is important for the pathogenesis of salt-sensitive hypertension. Full article
(This article belongs to the Special Issue Renin-Angiotensin System in Diseases)
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11 pages, 871 KiB  
Article
Angiotensin II-Induced Vasoconstriction via Rho Kinase Activation in Pressure-Overloaded Rat Thoracic Aortas
by Yuka Terada and Katsutoshi Yayama
Biomolecules 2021, 11(8), 1076; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11081076 - 21 Jul 2021
Cited by 5 | Viewed by 1829
Abstract
Angiotensin II (Ang II) induces vasoconstriction through myosin light chain (MLC) kinase activation and MLC phosphatase inactivation via phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) by Rho kinase. However, the detailed mechanism underlying Rho kinase activation by Ang II is still unknown. [...] Read more.
Angiotensin II (Ang II) induces vasoconstriction through myosin light chain (MLC) kinase activation and MLC phosphatase inactivation via phosphorylation of myosin phosphatase targeting subunit 1 (MYPT1) by Rho kinase. However, the detailed mechanism underlying Rho kinase activation by Ang II is still unknown. We investigated the mechanism of Ang II-induced vasoconstriction mediated by Rho kinase in pressure-overloaded rat thoracic aortas. Pressure-overloaded rats were produced by coarctation of the suprarenal abdominal aorta in four-week-old male Wistar rats. The contractile response to Ang II was significantly enhanced in the pressure-overloaded rats. Ang II-induced vasoconstriction was attenuated by inhibitors of Rho kinase, extracellular signal-regulated kinase 1 and 2 (Erk1/2), and epidermal growth factor receptor (EGFR) in both the sham-operated and pressure-overloaded rats. The Ang II-induced vasoconstriction was attenuated by a Janus kinase 2 (JAK2) inhibitor in only the pressure-overloaded rats. The protein levels of MYPT1 and JAK2 increased only in the pressure-overloaded rat thoracic aortas. These results suggested that Ang II-induced contraction is mediated by Rho kinase activation via EGFR, Erk1/2, and JAK2 in pressure-overloaded rat thoracic aortas. Moreover, Ang II-induced contraction was enhanced in pressure-overloaded rats probably because the protein levels of MYPT1 and JAK2 increased in the thoracic aortas. Full article
(This article belongs to the Special Issue Renin-Angiotensin System in Diseases)
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10 pages, 211 KiB  
Article
Gene Polymorphisms of the Renin-Angiotensin-Aldosterone System as Risk Factors for the Development of In-Stent Restenosis in Patients with Stable Coronary Artery Disease
by Madina Azova, Kalima Timizheva, Amira Ait Aissa, Mikhail Blagonravov, Olga Gigani, Anna Aghajanyan and Leyla Tskhovrebova
Biomolecules 2021, 11(5), 763; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11050763 - 20 May 2021
Cited by 11 | Viewed by 2471
Abstract
This study investigated the renin-angiotensin-aldosterone system (RAAS) gene polymorphisms as possible genetic risk factors for the restenosis development in patients with drug-eluting stents. 113 participants had coronary artery disease and underwent stenting. The control group consisted of 62 individuals with intact coronary arteries. [...] Read more.
This study investigated the renin-angiotensin-aldosterone system (RAAS) gene polymorphisms as possible genetic risk factors for the restenosis development in patients with drug-eluting stents. 113 participants had coronary artery disease and underwent stenting. The control group consisted of 62 individuals with intact coronary arteries. Patients were divided into two groups: with in-stent restenosis (ISR) and without it. The patients with ISR were classified into subgroups by the terms of the restenosis development and age. Real-time PCR and Restriction Fragment Length Polymorphism-PCR were used to genotype the study participants for RAAS gene polymorphisms. We found that the development of restenosis is generally associated with the minor A allele for renin (REN) rs2368564 and the major TT genotype for angiotensinogen (AGT) rs699. The heterozygous genotype for AGT rs4762 acts as a protective marker. A minor A allele for angiotensin II type 2 receptor (AGTR2) rs1403543 is associated with a risk of restenosis in people under 65 years old. Among patients with the early ISR, heterozygotes for angiotensin II type 1 receptor (AGTR1) rs5186 are more frequent, as well as A allele carriers for AGTR2 rs1403543. A minor homozygous genotype for REN rs41317140 and heterozygous genotype for aldosterone synthase (CYP11B2) rs1799998 are predisposed to the late restenosis. Thus, to choose the effective treatment tactics for patients with coronary artery disease, it is necessary to genotype patients for the RAAS polymorphisms, which, along with age and clinical characteristics, will allow a comprehensive assessment of the risk of the restenosis development after stenting. Full article
(This article belongs to the Special Issue Renin-Angiotensin System in Diseases)
14 pages, 2971 KiB  
Article
Expression of Components of the Renin-Angiotensin System by Cancer Stem Cells in Renal Clear Cell Carcinoma
by Sam Siljee, Bridget Milne, Helen D. Brasch, Nicholas Bockett, Josie Patel, Paul F. Davis, Andrew Kennedy-Smith, Tinte Itinteang and Swee T. Tan
Biomolecules 2021, 11(4), 537; https://0-doi-org.brum.beds.ac.uk/10.3390/biom11040537 - 07 Apr 2021
Cited by 9 | Viewed by 2412
Abstract
This study investigated the expression of components of the renin-angiotensin system (RAS) by cancer stem cells (CSCs) we have recently demonstrated in renal clear cell carcinoma (RCCC). Fifteen RCCC tissue samples underwent immunohistochemical staining for components of the RAS: renin, pro-renin receptor (PRR), [...] Read more.
This study investigated the expression of components of the renin-angiotensin system (RAS) by cancer stem cells (CSCs) we have recently demonstrated in renal clear cell carcinoma (RCCC). Fifteen RCCC tissue samples underwent immunohistochemical staining for components of the RAS: renin, pro-renin receptor (PRR), angiotensin-converting enzyme (ACE), angiotensin-converting enzyme 2 (ACE2), and angiotensin II receptor 2 (AT2R). Immunofluorescence co-staining or double immunohistochemical staining of these components of the RAS with stemness-associated markers OCT4 or KLF4 was performed on two of the samples. Protein and transcript expression of these components of the RAS in six RCCC tissue samples was investigated using western blotting and reverse transcription quantitative polymerase chain reaction (RT-qPCR), respectively. In addition, angiotensin II receptor 1 (AT1R) was investigated using RT-qPCR only. Immunohistochemical staining demonstrated expression of renin, PRR, and ACE2 in 11, 13, and 13 out of 15 RCCC samples, respectively, while AT2R was expressed in all 15 samples. ACE was detected in the endothelium of normal vasculature only. Double immunohistochemical staining demonstrated localization of ACE2, but not renin, to the KLF4+ CSCs. Immunofluorescence staining showed localization of PRR and AT2R to the OCT4+ CSCs. Western blotting confirmed protein expression of all components of the RAS except renin. RT-qPCR demonstrated transcript expression of all components of the RAS including AT1R, but not AT2R, in all six RCCC tissue samples. This study demonstrated expression of PRR, ACE2, and AT2R by the CSCs within RCCC. Further studies may lead to novel therapeutic targeting of CSCs by manipulation of the RAS in the treatment of this aggressive cancer. Full article
(This article belongs to the Special Issue Renin-Angiotensin System in Diseases)
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Review

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30 pages, 1117 KiB  
Review
Impact of the Renin-Angiotensin System on the Pathogeny and Pharmacotherapeutics of Neurodegenerative Diseases
by Walther Bild, Alexandru Vasincu, Răzvan-Nicolae Rusu, Daniela-Carmen Ababei, Aurelian Bogdan Stana, Gabriela Dumitrița Stanciu, Bogdan Savu and Veronica Bild
Biomolecules 2022, 12(10), 1429; https://0-doi-org.brum.beds.ac.uk/10.3390/biom12101429 - 06 Oct 2022
Cited by 4 | Viewed by 2298
Abstract
Brain neurodegenerative diseases (BND) are debilitating conditions that are especially characteristic of a certain period of life and considered major threats to human health. Current treatments are limited, meaning that there is a challenge in developing new options that can efficiently tackle the [...] Read more.
Brain neurodegenerative diseases (BND) are debilitating conditions that are especially characteristic of a certain period of life and considered major threats to human health. Current treatments are limited, meaning that there is a challenge in developing new options that can efficiently tackle the different components and pathophysiological processes of these conditions. The renin-angiotensin-aldosterone system (RAS) is an endocrine axis with important peripheral physiological functions such as blood pressure and cardiovascular homeostasis, as well as water and sodium balance and systemic vascular resistance—functions which are well-documented. However, recent work has highlighted the paracrine and autocrine functions of RAS in different tissues, including the central nervous system (CNS). It is known that RAS hyperactivation has pro-inflammatory and pro-oxidant effects, thus suggesting that its pharmacological modulation could be used in the management of these conditions. The present paper underlines the involvement of RAS and its components in the pathophysiology of BNDs such as Parkinson’s disease (PD), Alzheimer’s disease (AD), multiple sclerosis (MS), Huntington’s disease (HD), motor neuron disease (MND), and prion disease (PRD), as well as the identification of drugs and pharmacologically active substances that act upon RAS, which could alleviate their symptomatology or evolution, and thus, contribute to novel therapeutic approaches. Full article
(This article belongs to the Special Issue Renin-Angiotensin System in Diseases)
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