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Mahmod AI, Govindaraju K, Lokanathan Y, Said NABM, Ibrahim B. Exploring the Potential of Stem Cells in Modulating Gut Microbiota and Managing Hypertension. Stem Cells Dev 2025; 34:99-116. [PMID: 39836384 DOI: 10.1089/scd.2024.0195] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2025] Open
Abstract
Hypertension, commonly known as high blood pressure, is a significant health issue that increases the risk of cardiovascular diseases, stroke, and renal failure. This condition broadly encompasses both primary and secondary forms. Despite extensive research, the underlying mechanisms of systemic arterial hypertension-particularly primary hypertension, which has no identifiable cause and is affected by genetic and lifestyle agents-remain complex and not fully understood. Recent studies indicate that an imbalance in gut microbiota, referred to as dysbiosis, may promote hypertension, affecting blood pressure regulation through metabolites such as short-chain fatty acids and trimethylamine N-oxide. Current antihypertensive medications face limitations, including resistance and adherence issues, highlighting the need for novel therapeutic approaches. Stem cell therapy, an emerging field in regenerative medicine, shows promise in addressing these challenges. Stem cells, with mesenchymal stem cells being a prime example, have regenerative, anti-inflammatory, and immunomodulatory properties. Emerging research indicates that stem cells can modulate gut microbiota, reduce inflammation, and improve vascular health, potentially aiding in blood pressure management. Research has shown the positive impact of stem cells on gut microbiota in various disorders, suggesting their potential therapeutic role in treating hypertension. This review synthesizes the recent studies on the complex interactions between gut microbiota, stem cells, and systemic arterial hypertension. By offering a thorough analysis of the current literature, it highlights key insights, uncovers critical gaps, and identifies emerging trends that will inform and guide future investigations in this rapidly advancing field.
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Affiliation(s)
- Asma Ismail Mahmod
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, University of Malaya, Kuala Lumpur, Malaysia
| | - Kayatri Govindaraju
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, University of Malaya, Kuala Lumpur, Malaysia
| | - Yogeswaran Lokanathan
- Department of Tissue Engineering and Regenerative Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia, Kuala Lumpur, Malaysia
- Advance Bioactive Materials-Cells UKM Research Group, Universiti Kebangsaan Malaysia, Bangi, Malaysia
| | - Nur Akmarina B M Said
- Department of Pharmaceutical Life Sciences, Faculty of Pharmacy, University of Malaya, Kuala Lumpur, Malaysia
| | - Baharudin Ibrahim
- Department of Clinical Pharmacy and Pharmacy Practices, Faculty of Pharmacy, University Malaya, Kuala Lumpur, Malaysia
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Abreu MAD, de Castro PASV, Moreira FRC, de Oliveira Ferreira H, Simões E Silva AC. Potential Role of Novel Cardiovascular Biomarkers in Pediatric Patients with Chronic Kidney Disease. Mini Rev Med Chem 2024; 24:491-506. [PMID: 37231748 DOI: 10.2174/1389557523666230523114331] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/23/2023] [Revised: 04/15/2023] [Accepted: 04/26/2023] [Indexed: 05/27/2023]
Abstract
BACKGROUND Cardiovascular Disease is the leading cause of death in adult and pediatric patients with Chronic Kidney Disease (CKD) and its pathogenesis involves the interaction of multiple pathways. As Inflammatory mechanisms play a critical role in the vascular disease of CKD pediatric patients, there are several biomarkers related to inflammation strongly associated with this comorbidity. OBJECTIVE This review provides available evidence on the link between several biomarkers and the pathophysiology of heart disease in patients with CKD. METHODS The data were obtained independently by the authors, who carried out a comprehensive and non-systematic search in PubMed, Cochrane, Scopus, and SciELO databases. The search terms were "Chronic Kidney Disease", "Cardiovascular Disease", "Pediatrics", "Pathophysiology", "Mineral and Bone Disorder (MBD)", "Renin Angiotensin System (RAS)", "Biomarkers", "BNP", "NTproBNP", "CK-MB", "CXCL6", "CXCL16", "Endocan-1 (ESM-1)", "FABP3", "FABP4", h-FABP", "Oncostatin- M (OSM)", "Placental Growth Factor (PlGF)" and "Troponin I". RESULTS The pathogenesis of CKD-mediated cardiovascular disease is linked to inflammatory biomarkers, which play a critical role in the initiation, maintenance, and progression of cardiovascular disease. There are several biomarkers associated with cardiovascular disease in pediatric patients, including BNP, NTproBNP, CK-MB, CXCL6, CXCL16, Endocan-1 (ESM-1), FABP3, FABP4, Oncostatin- M (OSM), Placental Growth Factor (PlGF), and Troponin I. CONCLUSION The pathogenesis of CKD-mediated cardiovascular disease is not completely understood, but it is linked to inflammatory biomarkers. Further studies are required to elucidate the pathophysiological and potential role of these novel biomarkers.
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Affiliation(s)
- Maria Augusta Duarte Abreu
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
| | - Pedro Alves Soares Vaz de Castro
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
| | - Fernanda Rocha Chaves Moreira
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
| | - Henrique de Oliveira Ferreira
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
| | - Ana Cristina Simões E Silva
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
- Department of Pediatric Unit of Pediatric Nephrology, Faculty of Medicine UFMG, Belo Horizonte, Minas Gerais, Brazil
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de Miranda AS, Macedo DS, Rocha NP, Teixeira AL. Targeting the Renin-Angiotensin System (RAS) for Neuropsychiatric Disorders. Curr Neuropharmacol 2024; 22:107-122. [PMID: 36173067 PMCID: PMC10716884 DOI: 10.2174/1570159x20666220927093815] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2022] [Revised: 07/03/2022] [Accepted: 08/14/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Neuropsychiatric disorders, such as mood disorders, schizophrenia, and Alzheimer's disease (AD) and related dementias, are associated to significant morbidity and mortality worldwide. The pathophysiological mechanisms of neuropsychiatric disorders remain to be fully elucidated, which has hampered the development of effective therapies. The Renin Angiotensin System (RAS) is classically viewed as a key regulator of cardiovascular and renal homeostasis. The discovery that RAS components are expressed in the brain pointed out a potential role for this system in central nervous system (CNS) pathologies. The understanding of RAS involvement in the pathogenesis of neuropsychiatric disorders may contribute to identifying novel therapeutic targets. AIMS We aim to report current experimental and clinical evidence on the role of RAS in physiology and pathophysiology of mood disorders, schizophrenia, AD and related dementias. We also aim to discuss bottlenecks and future perspectives that can foster the development of new related therapeutic strategies. CONCLUSION The available evidence supports positive therapeutic effects for neuropsychiatric disorders with the inhibition/antagonism of the ACE/Ang II/AT1 receptor axis or the activation of the ACE2/Ang-(1-7)/Mas receptor axis. Most of this evidence comes from pre-clinical studies and clinical studies lag much behind, hampering a potential translation into clinical practice.
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Affiliation(s)
- Aline Silva de Miranda
- Interdisciplinary Laboratory of Medical Investigation (LIIM), Faculty of Medicine, UFMG, Belo Horizonte, MG, Brazil
- Department of Morphology, Laboratory of Neurobiology, Biological Science Institute, Federal University of Minas Gerais, Belo Horizonte, MG, Brazil
| | - Danielle S Macedo
- Department of Physiology and Pharmacology, Neuropharmacology Laboratory, Drug Research, and Development Center, Faculty of Medicine, Federal University of Ceara, Fortaleza, CE, Brazil
| | - Natalia P Rocha
- Department of Neurology, The Mitchell Center for Alzheimer's Disease and Related Brain Disorders, McGovern Medical School, University of Texas Health Science Center at Houston, TX, USA
| | - Antonio L Teixeira
- Department of Psychiatry and Behavioral Sciences, Neuropsychiatry Program, McGovern Medical School, University of Texas Health Science Center at Houston, TX, USA
- Faculdade Santa Casa BH, Belo Horizonte, Brasil
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Dabidi Roshan V, Ahmadian M, Nasiri K, Akbari A, Ghasemi M, Nasrollahi Borujeni N, Zahedmanesh F, Nabavi Chashmi SM, Imani F. Exercise-induced expression of SARS-CoV-2 entry receptors: impact of mask modality, sex, and exercise intensity. J Sports Med Phys Fitness 2023; 63:319-328. [PMID: 35686871 DOI: 10.23736/s0022-4707.22.14093-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
BACKGROUND Wearing a facemask affects physiological responses to exercise. We explored how exercising with a facemask affects the expression of SARS-CoV-2 entry receptor (angiotensin-converting enzyme 2 [ACE2]) and some associated genes (angiotensin type-1 receptors [AT1R]; Mas receptor [MasR]; hypoxia-inducible factor 1α [HIF-1α]; endothelial nitric oxide synthase [eNOS]) among healthy males and females. METHODS One hundred forty-four apparently healthy individuals (72 females; age: 30±6) were allocated to three mask groups of 48 (N95, Surgical, No Mask) with two exercise subgroups for each mask for both sexes. Participants in each experimental group performed either a submaximal (walking with no grade) or maximal (a modified Bruce Protocol) treadmill exercise test. Blood samples were collected before and after each exercise test and used to analyze the mRNA expression of the genes studied. RESULTS The post-exercise expression of genes examined were comparable between Surgical, N95, and No Mask (P>0.05). ACE2 was significantly greater in Surgical and N95 against No Mask at baseline and following moderate-intensity exercise (P<0.05). Whilst similar expressions were noted for MasR and eNOS (P>0.05), AT1R was greater in N95 than Surgical following high-intensity exercise (P<0.05). HIF-1α following either exercise intensity was significantly lower in N95 than Surgical (P<0.05). AT1R and HIF-1α were similar between Surgical and N95 against No Mask (P>0.05). ACE2 and AT1R were significantly higher in either mask modality than No Mask in males at baseline and postexercise (P<0.05). HIF-1α, MasR, and eNOS expressions were comparable between all mask groups in either sex (P<0.05). CONCLUSIONS Our findings suggest that wearing a facemask does not differentiate the gene expression of SARS-CoV-2 entry receptor following exercise among both sexes.
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Affiliation(s)
- Valiollah Dabidi Roshan
- Department of Exercise Physiology, Faculty of Sport Science, University of Mazandaran, Babolsar, Iran -
- Athletic Performance and Health Research Center, Faculty of Sport Science, University of Mazandaran, Babolsar, Iran -
| | - Mehdi Ahmadian
- School of Kinesiology, University of British Columbia, Vancouver, BC, Canada
| | - Khadijeh Nasiri
- Department of Exercise Physiology, Faculty of Sport Science, University of Mazandaran, Babolsar, Iran
| | - Abolfazl Akbari
- School of Veterinary Medicine, Department of Physiology, Shiraz University, Shiraz, Iran
| | - Mohammad Ghasemi
- Department of Exercise Physiology, Faculty of Sport Science, University of Mazandaran, Babolsar, Iran
| | | | - Foruzan Zahedmanesh
- Department of Exercise Physiology, Faculty of Sport Science, University of Mazandaran, Babolsar, Iran
| | - Seyedeh M Nabavi Chashmi
- Department of Exercise Physiology, Faculty of Sport Science, University of Mazandaran, Babolsar, Iran
| | - Fattaneh Imani
- Department of Exercise Physiology, Faculty of Sport Science, University of Mazandaran, Babolsar, Iran
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Araújo TSS, Santos CS, Soares JKB, Freitas JCR. Vitamin D: a potentially important secosteroid for coping with COVID-19. AN ACAD BRAS CIENC 2022; 94:e20201545. [PMID: 36000671 DOI: 10.1590/0001-3765202220201545] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2020] [Accepted: 01/28/2021] [Indexed: 12/15/2022] Open
Abstract
COVID-19 is a disease that has caused a high number of deaths in the world, and despite being controlled, it requires attention and the search for new quick and economical therapeutic strategies. In this sense, vitamin D stands out, an immunomodulator that has shown beneficial effects in decreasing the risk and severity of acute respiratory tract infections, including COVID-19. Therefore, this review presents a number of experimental, observational and clinical studies on the importance of vitamin D against viral infections with an emphasis on COVID-19, highlighting the relationship between vitamin D, Renin-Angiotensin System and cytokine storms with decreased inflammatory lesions in patients with COVID-19. In addition, aspects of pathophysiology, metabolism, risk factors, sources and recommendations of vitamin D are described. We conclude that vitamin D plays a protective role against inflammatory lesions and can decrease the risk of infections and the severity of COVID-19. Therefore, it is essential to maintain adequate levels of vitamin D to avoid complications related to its deficiency.
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Affiliation(s)
- Thayanne S S Araújo
- Universidade Federal de Campina Grande, Centro de Educação e Saúde, Rua Professora Maria Anita Furtado Coelho, s/n, Sítio Olho D'água da Bica, 58175-000 Cuité, PB, Brazil
| | - Cosme S Santos
- Universidade Federal Rural de Pernambuco, Departamento de Química, Rua Dom Manoel de Medeiros, s/n, 52171-900 Recife, PE, Brazil
| | - Juliana K B Soares
- Universidade Federal de Campina Grande, Centro de Educação e Saúde, Rua Professora Maria Anita Furtado Coelho, s/n, Sítio Olho D'água da Bica, 58175-000 Cuité, PB, Brazil
| | - Juliano C R Freitas
- Universidade Federal de Campina Grande, Centro de Educação e Saúde, Rua Professora Maria Anita Furtado Coelho, s/n, Sítio Olho D'água da Bica, 58175-000 Cuité, PB, Brazil.,Universidade Federal Rural de Pernambuco, Departamento de Química, Rua Dom Manoel de Medeiros, s/n, 52171-900 Recife, PE, Brazil
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Experimental Study on the Mechanism of Cinnamaldehyde Ameliorate Proteinuria Induced by Adriamycin. BIOMED RESEARCH INTERNATIONAL 2022; 2022:9600450. [PMID: 35993052 PMCID: PMC9385347 DOI: 10.1155/2022/9600450] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/06/2022] [Revised: 07/07/2022] [Accepted: 07/13/2022] [Indexed: 11/17/2022]
Abstract
Objective. Cinnamaldehyde (CA) is the main active component of Guizhi (Cinnamomi ramulus) to ameliorate adriamycin- (ADR-) induced proteinuria in rats. However, the underlying mechanism of CA against proteinuria remains unclear. The aim of this study was to investigate the action mechanisms of CA to treat proteinuria. Methods. 13 rats were randomly selected from 78 SD rats as control group, and the other rats were injected with ADR (3 mg/kg/time) twice through tail vein on day 1 and day 8 for modeling. After modeling, the rats were randomly divided into 5 groups as follows: ADR group, ADR+CA low-dose group, ADR+CA middle-dose group, ADR+CA high-dose group and Benazepril group with 13 rats in each group. The urine of SD rats was collected for 24 h, urine protein, creatinine and urea nitrogen were detected, renal index was calculated, and HE staining and western blot were performed. Results. The 24 h urine volume and urine protein, renal function, and renal histopathology got worse significantly in the ADR group. To western blot, CA downregulated the protein expression of ACE and Ang-2 and upregulated the protein expression of ACE2 in RAS signaling pathway. Conclusion. The underlying action mechanism of CA to treat NS might mainly be achieved by regulating RAS signaling pathway.
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Correa BHM, Becari L, Peliky Fontes MA, Simões-e-Silva AC, Kangussu LM. Involvement of the Renin-Angiotensin System in Stress: State of the Art and Research Perspectives. Curr Neuropharmacol 2022; 20:1212-1228. [PMID: 34554902 PMCID: PMC9886820 DOI: 10.2174/1570159x19666210719142300] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 06/19/2021] [Accepted: 07/09/2021] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Along with other canonical systems, the renin-angiotensin system (RAS) has shown important roles in stress. This system is a complex regulatory proteolytic cascade composed of various enzymes, peptides, and receptors. Besides the classical (ACE/Ang II/AT1 receptor) and the counter-regulatory (ACE2/Ang-(1-7)/Mas receptor) RAS axes, evidence indicates that nonclassical components, including Ang III, Ang IV, AT2 and AT4, can also be involved in stress. OBJECTIVE AND METHODS This comprehensive review summarizes the current knowledge on the participation of RAS components in different adverse environmental stimuli stressors, including air jet stress, cage switch stress, restraint stress, chronic unpredictable stress, neonatal isolation stress, and post-traumatic stress disorder. RESULTS AND CONCLUSION In general, activation of the classical RAS axis potentiates stress-related cardiovascular, endocrine, and behavioral responses, while the stimulation of the counter-regulatory axis attenuates these effects. Pharmacological modulation in both axes is optimistic, offering promising perspectives for stress-related disorders treatment. In this regard, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are potential candidates already available since they block the classical axis, activate the counter-regulatory axis, and are safe and efficient drugs.
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Affiliation(s)
- Bernardo H. M. Correa
- Department of Morphology, Biological Sciences Institute, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil;
| | - Luca Becari
- Department of Morphology, Biological Sciences Institute, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil;
| | - Marco Antônio Peliky Fontes
- Department of Physiology & Biophysics - Biological Sciences Institute, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil;
| | - Ana Cristina Simões-e-Silva
- Department of Pediatrics, Faculty of Medicine, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil
| | - Lucas M. Kangussu
- Department of Morphology, Biological Sciences Institute, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil; ,Address correspondence to this author at the Department of Morphology, Biological Sciences Institute – Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Brazil; Tel: (+55-31) 3409-2772; E-mail:
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Wu J, Sun Z, Yang S, Fu J, Fan Y, Wang N, Hu J, Ma L, Peng C, Wang Z, Lee K, He JC, Li Q. Kidney single-cell transcriptome profile reveals distinct response of proximal tubule cells to SGLT2i and ARB treatment in diabetic mice. Mol Ther 2022; 30:1741-1753. [PMID: 34678510 PMCID: PMC9077318 DOI: 10.1016/j.ymthe.2021.10.013] [Citation(s) in RCA: 37] [Impact Index Per Article: 12.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2021] [Revised: 08/30/2021] [Accepted: 10/13/2021] [Indexed: 12/20/2022] Open
Abstract
Angiotensin receptor blockers (ARBs) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) have been used as the standard therapy for patients with diabetic kidney disease (DKD). However, how these two drugs possess additive renoprotective effects remains unclear. Here, we conducted single-cell RNA sequencing to profile the kidney cell transcriptome of db/db mice treated with vehicle, ARBs, SGLT2i, or ARBs plus SGLT2i, using db/m mice as control. We identified 10 distinct clusters of kidney cells with predominant proximal tubular (PT) cells. We found that ARBs had more anti-inflammatory and anti-fibrotic effects, while SGLT2i affected more mitochondrial function in PT. We also identified a new PT subcluster, was increased in DKD, but reversed by the treatments. This new subcluster was also confirmed by immunostaining of mouse and human kidneys with DKD. Together, our study reveals kidney cell-specific gene signatures in response to ARBs and SGLT2i and identifies a new PT subcluster, which provides new insight into the pathogenesis of DKD.
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Affiliation(s)
- Jinshan Wu
- Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Zeguo Sun
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - Shumin Yang
- Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Jia Fu
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - Ying Fan
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Niansong Wang
- Department of Nephrology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai 200233, China
| | - Jinbo Hu
- Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Linqiang Ma
- Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Chuan Peng
- Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Zhihong Wang
- Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China
| | - Kyung Lee
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY 10029, USA
| | - John Cijiang He
- Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, NY 10029, USA; Renal Program, James J Peters VA Medical Center at Bronx, NY 10468, USA.
| | - Qifu Li
- Department of Endocrinology, the First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
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Abstract
It is hypothesized that several comorbidities increase the severity of COVID-19 symptoms. Cardiovascular disease including hypertension was shown to play a critical role in the severity of COVID-19 infection by affecting the survival of patients with COVID-19. Hypertension and the renin-angiotensin-aldosterone system are involved in increasing vascular inflammation and endothelial dysfunction (ED), and both processes are instrumental in COVID-19. Angiotensin-converting enzyme 2 is an essential component of the renin-angiotensin-aldosterone system and the target receptor that mediates SARS-CoV-2 entry to the cell. This led to speculations that major renin-angiotensin-aldosterone system inhibitors, such as angiotensin receptor blockers and angiotensin-converting enzyme inhibitors might affect the course of the disease, since their administration enhances angiotensin-converting enzyme (ACE)2 expression. An increase in ACE2 activity could reduce angiotensin II concentration in the lungs and mitigate virus-driven lung injury. This could also be associated with a reduction in blood coagulation, which plays a critical role in the pathogenesis of SARS-CoV-2; of note, COVID-19 is now regarded as a disorder of blood clotting. Therefore, there is an urgent need to better understand the effect of targeting ACE2 as a potential treatment for SARS-CoV-2 driven injury, and in alleviating COVID-19 symptoms by reversing SARS-CoV-2-induced excessive coagulation and fatalities. Ongoing therapeutic strategies that include recombinant human ACE2 and anti-spike monoclonal antibodies are essential for future clinical practice in order to better understand the effect of targeting ED in COVID-19.
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Affiliation(s)
- Jalil Daher
- Department of Biology, Faculty of Arts and Sciences, University of Balamand, Tripoli PO Box 100, Lebanon
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Diniz LRL, Elshabrawy HA, Souza MTDS, Duarte ABS, Datta S, de Sousa DP. Catechins: Therapeutic Perspectives in COVID-19-Associated Acute Kidney Injury. Molecules 2021; 26:5951. [PMID: 34641495 PMCID: PMC8512361 DOI: 10.3390/molecules26195951] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2021] [Revised: 09/21/2021] [Accepted: 09/22/2021] [Indexed: 12/14/2022] Open
Abstract
Data obtained from several intensive care units around the world have provided substantial evidence of the strong association between impairment of the renal function and in-hospital deaths of critically ill COVID-19 patients, especially those with comorbidities and requiring renal replacement therapy (RRT). Acute kidney injury (AKI) is a common renal disorder of various etiologies characterized by a sudden and sustained decrease of renal function. Studies have shown that 5-46% of COVID-19 patients develop AKI during hospital stay, and the mortality of those patients may reach up to 100% depending on various factors, such as organ failures and RRT requirement. Catechins are natural products that have multiple pharmacological activities, including anti-coronavirus and reno-protective activities against kidney injury induced by nephrotoxic agents, obstructive nephropathies and AKI accompanying metabolic and cardiovascular disorders. Therefore, in this review, we discuss the anti-SARS-CoV-2 and reno-protective effects of catechins from a mechanistic perspective. We believe that catechins may serve as promising therapeutics in COVID-19-associated AKI due to their well-recognized anti-SARS-CoV-2, and antioxidant and anti-inflammatory properties that mediate their reno-protective activities.
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Affiliation(s)
| | - Hatem A. Elshabrawy
- Department of Molecular and Cellular Biology, College of Osteopathic Medicine, Sam Houston State University, Conroe, TX 77304, USA;
| | | | | | - Sabarno Datta
- College of Osteopathic Medicine, Sam Houston State University, Conroe, TX 77304, USA;
| | - Damião Pergentino de Sousa
- Department of Pharmaceutical Sciences, Federal University of Paraíba, João Pessoa 58051-970, PB, Brazil;
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Ahmad A, Raish M, Alkharfy KM. The potential role of thymoquinone in preventing the cardiovascular complications of COVID-19. Vascul Pharmacol 2021; 141:106899. [PMID: 34311073 PMCID: PMC8299308 DOI: 10.1016/j.vph.2021.106899] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Revised: 06/07/2021] [Accepted: 07/20/2021] [Indexed: 01/20/2023]
Abstract
A new virus strain detected in late 2019 and not previously described in humans is the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which causes corona virus disease (COVID-19). While potential therapeutic approaches for COVID-19 are being investigated, significant initiatives are being made to create protective drugs and study various antiviral agents to cure the infection. However, an effective treatment strategy against COVID-19 is worrisome inadequate. The objective of the present manuscript is to discuss the potential role of thymoquinone (TQ) in preventing the cardiovascular complications of COVID-19, focusing on viral inhibition, antioxidant potential, vascular effect, and cardiac protection. The multifunctional properties of TQ could potentially synergize with the activity of current therapeutic interventions and offer a basis for managing COVID-19 disease more effectively. Even though the experimental evidence is positive, a translational application of TQ in COVID-19 is timely warranted.
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Affiliation(s)
- Ajaz Ahmad
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Mohammad Raish
- Department of Pharmaceutics, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia
| | - Khalid M Alkharfy
- Department of Clinical Pharmacy, College of Pharmacy, King Saud University, Riyadh 11451, Saudi Arabia.
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Belisário AR, S Filha RD, de Almeida JA, Mendes FG, Rezende PV, Vieira ÉL, E Silva AC. Novel kidney injury biomarkers in a large cohort of children with sickle cell anemia. Biomark Med 2021; 15:999-1009. [PMID: 34289712 DOI: 10.2217/bmm-2020-0769] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/21/2022] Open
Abstract
Aim: The aim of this study was to compare novel kidney injury biomarkers in sickle cell anemia (SCA) children with and without albuminuria or glomerular hyperfiltration. Materials & methods: A total of 358 Brazilian children with SCA were studied. Fifteen kidney injury biomarkers in urine were measured. Albuminuria was defined as urine albumin/creatinine ratio >100 mg/g. Glomerular hyperfiltration was defined as estimated glomerular filtration rate ≥140 ml/min/1.73 m2. Results: After adjustment for age, sex and modifying therapies in use, EGF and collagen IV urinary levels were associated with albuminuria. Renin and clusterin levels were associated with hyperfiltration. Conclusion: Levels of novel kidney injury biomarkers were associated with albuminuria and hyperfiltration in Brazilian children with SCA, suggesting concomitant structural and functional abnormalities.
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Affiliation(s)
- André R Belisário
- Centro de Tecidos Biológicos de Minas Gerais, Fundação Hemominas, Lagoa Santa, Minas Gerais, 33400000, Brazil.,Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, 30130100, Brazil.,Faculdade de Medicina/Núcleo de Ações e Pesquisa em Apoio Diagnóstico (NUPAD), UFMG, Belo Horizonte, Minas Gerais, 30130100, Brazil
| | - Roberta da S Filha
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, 30130100, Brazil
| | - Jéssica A de Almeida
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, 30130100, Brazil
| | - Fabíola G Mendes
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, 30130100, Brazil
| | - Paulo V Rezende
- Faculdade de Medicina/Núcleo de Ações e Pesquisa em Apoio Diagnóstico (NUPAD), UFMG, Belo Horizonte, Minas Gerais, 30130100, Brazil.,Ambulatório do Hemocentro de Belo Horizonte, Fundação Hemominas, Belo Horizonte, Minas Gerais, 30130110, Brazil
| | - Érica Lm Vieira
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, 30130100, Brazil
| | - Ana Cs E Silva
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, 30130100, Brazil
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13
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Simões E Silva AC, Lanza K, Palmeira VA, Costa LB, Flynn JT. 2020 update on the renin-angiotensin-aldosterone system in pediatric kidney disease and its interactions with coronavirus. Pediatr Nephrol 2021; 36:1407-1426. [PMID: 32995920 PMCID: PMC7524035 DOI: 10.1007/s00467-020-04759-1] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 08/12/2020] [Accepted: 09/03/2020] [Indexed: 12/16/2022]
Abstract
The last decade was crucial for our understanding of the renin-angiotensin-aldosterone system (RAAS) as a two-axis, counter-regulatory system, divided into the classical axis, formed by angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and the angiotensin type 1 receptor (AT1R), and the alternative axis comprising angiotensin-converting enzyme 2 (ACE2), angiotensin-(1-7) (Ang-(1-7)), and the Mas receptor. Breakthrough discoveries also took place, with other RAAS endopeptides being described, including alamandine and angiotensin A. In this review, we characterize the two RAAS axes and the role of their components in pediatric kidney diseases, including childhood hypertension (HTN), pediatric glomerular diseases, congenital abnormalities of the kidney and urinary tract (CAKUT), and chronic kidney disease (CKD). We also present recent findings on potential interactions between the novel coronavirus, SARS-CoV-2, and components of the RAAS, as well as potential implications of coronavirus disease 2019 (COVID-19) for pediatric kidney diseases.
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Affiliation(s)
- Ana Cristina Simões E Silva
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Avenida Alfredo Balena, 190, 2nd floor, Room # 281, Belo Horizonte, MG, 30130-100, Brazil.
- Pediatric Nephrology Unit, Department of Pediatrics, Faculty of Medicine, UFMG, Belo Horizonte, Brazil.
| | - Katharina Lanza
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Avenida Alfredo Balena, 190, 2nd floor, Room # 281, Belo Horizonte, MG, 30130-100, Brazil
| | - Vitória Andrade Palmeira
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Avenida Alfredo Balena, 190, 2nd floor, Room # 281, Belo Horizonte, MG, 30130-100, Brazil
| | - Larissa Braga Costa
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais (UFMG), Avenida Alfredo Balena, 190, 2nd floor, Room # 281, Belo Horizonte, MG, 30130-100, Brazil
| | - Joseph T Flynn
- Pediatric Nephrology, Seattle Children's Hospital, University of Washington School of Medicine, Seattle, WA, 98105, USA
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14
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Abstract
The novel 2019 coronavirus disease (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is a highly transmissible and pathogenic coronavirus. Because of the novelty of the COVID-19 pandemic, few data are available on the impact of the SARS-CoV-2 on the different endocrine glands. Previous studies of severe acute respiratory syndrome (SARS) have shown a harmful effect on endocrine function. Notably, the angiotensin-converting enzyme-2 receptor, which is the entry route of coronaviruses to the host cell, is widely expressed in the endocrine organs including testis, endocrine pancreas, thyroid, and adrenal, and pituitary glands. Clinical and biochemical manifestations have been recorded in COVID-19 patients resulting in changes in endocrine activities, which were also recorded during the SARS outbreak in 2003. This review aims to explore the impact of SARS-CoV-2 infection on the function of endocrine glands, based on the latest research in the field.
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Affiliation(s)
- Adel Abdel-Moneim
- Molecular Physiology Division, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
| | - Ahmed Hosni
- Molecular Physiology Division, Faculty of Science, Beni-Suef University, Beni-Suef, Egypt
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15
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Pousa PA, Mendonça TSC, Oliveira EA, Simões-E-Silva AC. Extrapulmonary manifestations of COVID-19 in children: a comprehensive review and pathophysiological considerations. J Pediatr (Rio J) 2021; 97:116-139. [PMID: 32980319 PMCID: PMC7508521 DOI: 10.1016/j.jped.2020.08.007] [Citation(s) in RCA: 31] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2020] [Accepted: 08/25/2020] [Indexed: 12/16/2022] Open
Abstract
OBJECTIVE The aim of this review was to summarize the most common extrapulmonary manifestations in pediatric patients with COVID-19, as well as to discuss clinical, epidemiological, and pathophysiological aspects of these clinical presentations in children. SOURCE OF DATA An extensive search of literature was performed in order to identify pediatric cases with extrapulmonary manifestations between January 1, 2020 and June 21, 2020. Generic keywords, such as "Novel coronavirus" or "Novel coronavirus 2019" or "2019 nCoV" or "COVID-19" or "SARS-CoV-2" were searched on PubMed database, associated either with age filters or generic pediatric terms. SUMMARY OF FINDINGS A total of 28 articles, including 199 patients, were considered suitable to review and data extraction. The main findings were summarized in tables. The main non-pulmonary manifestations in pediatric patients, in decreasing order of frequency, were gastrointestinal, renal, cardiovascular, neurological, hematological and lymphatic, cutaneous, hepatic, ocular, olfactory, and gustatory. Multisystem impairment and Kawasaki-like disease were also described. CONCLUSIONS Differences in immune response of children and variations of tissue expression of angiotensin converting enzyme 2, the virus receptor, are likely to influence clinical, epidemiological, and pathophysiological patterns of the disease.
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Affiliation(s)
- Pedro A Pousa
- Universidade Federal de Minas Gerais (UFMG), Faculdade de Medicina, Laboratório Interdisciplinar de Pesquisa Médica, Belo Horizonte, MG, Brazil
| | - Tamires S C Mendonça
- Universidade Federal de Minas Gerais (UFMG), Faculdade de Medicina, Laboratório Interdisciplinar de Pesquisa Médica, Belo Horizonte, MG, Brazil
| | - Eduardo A Oliveira
- Universidade Federal de Minas Gerais (UFMG), Faculdade de Medicina, Departamento de Pediatria, Unidade de Nefrologia Pediátrica, Belo Horizonte, MG, Brazil
| | - Ana Cristina Simões-E-Silva
- Universidade Federal de Minas Gerais (UFMG), Faculdade de Medicina, Laboratório Interdisciplinar de Pesquisa Médica, Belo Horizonte, MG, Brazil; Universidade Federal de Minas Gerais (UFMG), Faculdade de Medicina, Departamento de Pediatria, Unidade de Nefrologia Pediátrica, Belo Horizonte, MG, Brazil.
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16
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Bitencourt L, Pedrosa AL, de Brito SBCS, Fróes ACF, de Carvalho ST, Fonseca GG, Ferreira GC, Fradico PF, Simões E Silva AC. COVID-19 and Renal Diseases: An Update. Curr Drug Targets 2021; 22:52-67. [PMID: 33050860 DOI: 10.2174/1389450121999201013151300] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2020] [Revised: 09/04/2020] [Accepted: 09/04/2020] [Indexed: 02/08/2023]
Abstract
BACKGROUND It becomes increasingly evident that the SARS-CoV-2 infection is not limited to the respiratory system. In addition to being a target of the virus, the kidney also seems to have a substantial influence on the outcomes of the disease. METHODS Data was obtained by a comprehensive and non-systematic search in the PubMed, Cochrane, Scopus and SciELO databases, using mainly the terms "SARS-CoV-2", "COVID-19", "chronic kidney disease", "renal transplantation", acute kidney injury" and "renal dysfunction" Discussion: The membrane-bound angiotensin-converting enzyme 2 is the receptor for SARS-CoV- -2, and this interaction may lead to an imbalance of the Renin-Angiotensin System (RAS), associated with worse clinical presentations of COVID-19, including acute pulmonary injury, hyperinflammatory state and hematological alterations. In the framework of renal diseases, the development of acute kidney injury is associated mostly with immune alterations and direct cytopathic lesions by the virus, leading to higher mortality. As for chronic kidney disease, the patients at a non-terminal stage have a worse prognosis, while the hemodialysis patients appear to have mild courses of COVID-19, probably due to lower chances of being affected by the cytokine storm. Furthermore, the current scenario is unfavorable to kidney donation and transplantation. The relationship between COVID-19 and immunosuppression in kidney transplantation recipients has been greatly discussed to determine whether it increases mortality and how it interacts with immunosuppressive medications. CONCLUSION The kidney and the RAS exert fundamental roles in the SARS-CoV-2 infection, and more research is required to have a complete understanding of the repercussions caused by COVID-19 in renal diseases.
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Affiliation(s)
- Letícia Bitencourt
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, UFMG, Belo Horizonte, Minas Gerais, Brazil
| | - Ana Luisa Pedrosa
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, UFMG, Belo Horizonte, Minas Gerais, Brazil
| | - Stephanie Bruna Camilo Soares de Brito
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, UFMG, Belo Horizonte, Minas Gerais, Brazil
| | - Ana Cláudia Fontoura Fróes
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, UFMG, Belo Horizonte, Minas Gerais, Brazil
| | - Sarah Tayná de Carvalho
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, UFMG, Belo Horizonte, Minas Gerais, Brazil
| | - Giulio Gori Fonseca
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, UFMG, Belo Horizonte, Minas Gerais, Brazil
| | - Guilherme Costa Ferreira
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, UFMG, Belo Horizonte, Minas Gerais, Brazil
| | - Pollyanna Faria Fradico
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, UFMG, Belo Horizonte, Minas Gerais, Brazil
| | - Ana Cristina Simões E Silva
- Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Federal University of Minas Gerais, UFMG, Belo Horizonte, Minas Gerais, Brazil
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17
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Barbosa IG, Ferreira GC, Andrade Júnior DF, Januário CR, Belisário AR, Bauer ME, Simões E Silva AC. The Renin Angiotensin System and Bipolar Disorder: A Systematic Review. Protein Pept Lett 2020; 27:520-528. [PMID: 32003654 DOI: 10.2174/0929866527666200127115059] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/08/2019] [Revised: 09/07/2019] [Accepted: 11/16/2019] [Indexed: 12/27/2022]
Abstract
Bipolar Disorder (BD) is a chronic a multifactorial psychiatric illness that affects mood, cognition, and functioning. BD is associated with several psychiatric conditions as well clinical comorbidities, particularly cardiovascular diseases. The neurobiology of BD is complex and multifactorial and several systems have been implicated. Considering that the Renin Angiotensin System (RAS) plays an important role in cardiovascular diseases and that recently evidence has suggested its role in psychiatric disorders, the aim of the present study is to summarize and to discuss recent findings related to the modulation of RAS components in BD. A systematic search of the literature using the electronic databases MEDLINE and LILACS was conducted through March 2019. The search terms were: "Bipolar Disorder"; "Renin Angiotensin System"; "Angiotensin 2"; "Angiotensin receptors"; "Angiotensin 1-7"; "ACE"; "ACE2"; "Mas Receptor". We included original studies assessing RAS in BD patients. Two hundred twenty-two citations were initially retrieved. Eleven studies were included in our systematic review. In the majority of studies (6 of 8), the ACE insertion/deletion (I/D) polymorphism did not differ between BD patients and controls. BD patients presented higher plasma renin activity in comparison with controls. The studies evaluating the RAS molecules in BD are very scarce and heterogeneous. The literature suggests a potential role of RAS in BD. Further studies are necessary to investigate this relationship.
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Affiliation(s)
- Izabela Guimarães Barbosa
- Interdisciplinary Laboratory of Medical Investigation - Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Giulia Campos Ferreira
- Interdisciplinary Laboratory of Medical Investigation - Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Diomildo Ferreira Andrade Júnior
- Interdisciplinary Laboratory of Medical Investigation - Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Cássio Rocha Januário
- Interdisciplinary Laboratory of Medical Investigation - Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - André Rolim Belisário
- Interdisciplinary Laboratory of Medical Investigation - Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
| | - Moises Evandro Bauer
- Laboratory of Immunosenescence, Graduate Program in Biomedical Gerontology, School of Sciences, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil.,School of Sciences, Pontifícia Universidade Católica do Rio Grande do Sul (PUCRS), Porto Alegre, Brazil
| | - Ana Cristina Simões E Silva
- Interdisciplinary Laboratory of Medical Investigation - Faculty of Medicine, Federal University of Minas Gerais (UFMG), Belo Horizonte, MG, Brazil
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18
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Costa LB, Perez LG, Palmeira VA, Macedo e Cordeiro T, Ribeiro VT, Lanza K, Simões e Silva AC. Insights on SARS-CoV-2 Molecular Interactions With the Renin-Angiotensin System. Front Cell Dev Biol 2020; 8:559841. [PMID: 33042994 PMCID: PMC7525006 DOI: 10.3389/fcell.2020.559841] [Citation(s) in RCA: 43] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2020] [Accepted: 08/25/2020] [Indexed: 12/15/2022] Open
Abstract
The emergence of SARS-CoV-2/human/Wuhan/X1/2019, a virus belonging to the species Severe acute respiratory syndrome-related coronavirus, and the recognition of Coronavirus Disease 2019 (COVID-19) as a pandemic have highly increased the scientific research regarding the pathogenesis of COVID-19. The Renin Angiotensin System (RAS) seems to be involved in COVID-19 natural course, since studies suggest the membrane-bound Angiotensin-converting enzyme 2 (ACE2) works as SARS-CoV-2 cellular receptor. Besides the efforts of the scientific community to understand the virus' molecular interactions with human cells, few studies summarize what has been so far discovered about SARS-CoV-2 signaling mechanisms and its interactions with RAS molecules. This review aims to discuss possible SARS-CoV-2 intracellular signaling pathways, cell entry mechanism and the possible consequences of the interaction with RAS components, including Angiotensin II (Ang II), Angiotensin-(1-7) [Ang-(1-7)], Angiotensin-converting enzyme (ACE), ACE2, Angiotensin II receptor type-1 (AT1), and Mas Receptor. We also discuss ongoing clinical trials and treatment based on RAS cascade intervention. Data were obtained independently by the two authors who carried out a search in the PubMed, Embase, LILACS, Cochrane, Scopus, SciELO and the National Institute of Health databases using Medical Subject Heading terms as "SARS-CoV-2," "COVID-19," "Renin Angiotensin System," "ACE2," "Angiotensin II," "Angiotensin-(1-7)," and "AT1 receptor." Similarly to other members of Coronaviridae family, the molecular interactions between the pathogen and the membrane-bound ACE2 are based on the cleavage of the spike glycoprotein (S) in two subunits. Following the binding of the S1 receptor-binding domain (RBD) to ACE2, transmembrane protease/serine subfamily 2 (TMPRSS2) cleaves the S2 domain to facilitate membrane fusion. It is very likely that SARS-CoV-2 cell entry results in downregulation of membrane-bound ACE2, an enzyme that converts Ang II into Ang-(1-7). This mechanism can result in lung injury and vasoconstriction. In addition, Ang II activates pro-inflammatory cascades when binding to the AT1 Receptor. On the other hand, Ang-(1-7) promotes anti-inflammatory effects through its interactions with the Mas Receptor. These molecules might be possible therapeutic targets for treating COVID-19. Thus, the understanding of SARS-CoV-2 intracellular pathways and interactions with the RAS may clarify COVID-19 physiopathology and open perspectives for new treatments and strategies.
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19
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de Miranda AS, Teixeira AL. Coronavirus Disease-2019 Conundrum: RAS Blockade and Geriatric-Associated Neuropsychiatric Disorders. Front Med (Lausanne) 2020; 7:515. [PMID: 32850927 PMCID: PMC7431869 DOI: 10.3389/fmed.2020.00515] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/04/2020] [Accepted: 07/24/2020] [Indexed: 01/08/2023] Open
Abstract
Coronavirus Disease 2019 (COVID-19) is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), which primarily targets the human respiratory system and may lead to severe pneumonia and ultimately death. Mortality rate is particurlarly high among people beyond the sixth decade of life with cardiovascular and metabolic diseases. The discovery that the SARS-CoV-2 uses the renin-angiotensin system (RAS) component ACE2 as a receptor to invade host epithelial cells and cause organs damage resulted in a debate regarding the role of ACE inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) therapies during COVID-19 pandemic. Some authors proposed the discontinuation of ACEIs and ARBs for cardiovascular, kidney, and metabolic diseases, while expert opinions have discouraged that due to limited empirical evidence of their negative effect on COVID-19 outcomes, and that withdrawing treatment may contribute to clinical decompensation in high-risk patients. Moreover, as cardiovascular and metabolic diseases are associated with neurodegenerative and psychiatric disorders, especially among older adults, a critical appraisal of the potential positive effects of ACEIs and ARBs is highly needed. Herein, we aim to discuss the conundrum of ACEIs and ARBs use in high-risk patients for COVID-19, and their potential protective role on the development and/or progression of geriatric neuropsychiatric disorders.
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Affiliation(s)
- Aline Silva de Miranda
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil.,Laboratório de Neurobiologia, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
| | - Antonio Lucio Teixeira
- Instituto de Ensino e Pesquisa Santa Casa BH, Belo Horizonte, Brazil.,Neuropsychiatry Program, Department of Psychiatry and Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, United States
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20
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South AM, Brady TM, Flynn JT. ACE2 (Angiotensin-Converting Enzyme 2), COVID-19, and ACE Inhibitor and Ang II (Angiotensin II) Receptor Blocker Use During the Pandemic: The Pediatric Perspective. Hypertension 2020; 76:16-22. [PMID: 32367746 PMCID: PMC7289676 DOI: 10.1161/hypertensionaha.120.15291] [Citation(s) in RCA: 88] [Impact Index Per Article: 17.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
Potential but unconfirmed risk factors for coronavirus disease 2019 (COVID-19) in adults and children may include hypertension, cardiovascular disease, and chronic kidney disease, as well as the medications commonly prescribed for these conditions, ACE (angiotensin-converting enzyme) inhibitors, and Ang II (angiotensin II) receptor blockers. Coronavirus binding to ACE2 (angiotensin-converting enzyme 2), a crucial component of the renin-angiotensin-aldosterone system, underlies much of this concern. Children are uniquely impacted by the coronavirus, but the reasons are unclear. This review will highlight the relationship of COVID-19 with hypertension, use of ACE inhibitors and Ang II receptor blockers, and lifetime risk of cardiovascular disease from the pediatric perspective. We briefly summarize the renin-angiotensin-aldosterone system and comprehensively review the literature pertaining to the ACE 2/Ang-(1-7) pathway in children and the clinical evidence for how ACE inhibitors and Ang II receptor blockers affect this important pathway. Given the importance of the ACE 2/Ang-(1-7) pathway and the potential differences between adults and children, it is crucial that children are included in coronavirus-related research, as this may shed light on potential mechanisms for why children are at decreased risk of severe COVID-19.
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Affiliation(s)
- Andrew M. South
- Section of Nephrology, Department of Pediatrics, Wake Forest School of Medicine and Brenner Children’s Hospital
- Department of Surgery-Hypertension and Vascular Research, Wake Forest School of Medicine
- Department of Epidemiology and Prevention, Division of Public Health Sciences, Wake Forest School of Medicine
- Cardiovascular Sciences Center, Wake Forest School of Medicine, Winston Salem, NC
| | - Tammy M. Brady
- Division of Nephrology, Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, MD
| | - Joseph T. Flynn
- Department of Pediatrics, University of Washington School of Medicine and Division of Nephrology, Seattle Children’s Hospital, Seattle, WA, USA
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21
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Morphological and Functional Characteristics of Animal Models of Myocardial Fibrosis Induced by Pressure Overload. Int J Hypertens 2020; 2020:3014693. [PMID: 32099670 PMCID: PMC7013318 DOI: 10.1155/2020/3014693] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/26/2019] [Revised: 12/07/2019] [Accepted: 12/16/2019] [Indexed: 02/07/2023] Open
Abstract
Myocardial fibrosis is characterized by excessive deposition of myocardial interstitial collagen, abnormal distribution, and excessive proliferation of fibroblasts. According to the researches in recent years, myocardial fibrosis, as the pathological basis of various cardiovascular diseases, has been proven to be a core determinant in ventricular remodeling. Pressure load is one of the causes of myocardial fibrosis. In experimental models of pressure-overload-induced myocardial fibrosis, significant increase in left ventricular parameters such as interventricular septal thickness and left ventricular posterior wall thickness and the decrease of ejection fraction are some of the manifestations of cardiac damage. These morphological and functional changes have a serious impact on the maintenance of physiological functions. Therefore, establishing a suitable myocardial fibrosis model is the basis of its pathogenesis research. This paper will discuss the methods of establishing myocardial fibrosis model and compare the advantages and disadvantages of the models in order to provide a strong basis for establishing a myocardial fibrosis model.
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22
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Magalhães DM, Nunes-Silva A, Rocha GC, Vaz LN, de Faria MHS, Vieira ELM, Rocha NP, Simões e Silva AC. Two protocols of aerobic exercise modulate the counter-regulatory axis of the renin-angiotensin system. Heliyon 2020; 6:e03208. [PMID: 31989052 PMCID: PMC6970173 DOI: 10.1016/j.heliyon.2020.e03208] [Citation(s) in RCA: 34] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/17/2019] [Revised: 09/17/2019] [Accepted: 01/09/2020] [Indexed: 12/30/2022] Open
Abstract
AIMS The renin-angiotensin system (RAS) is a dual system with two opposite arms: i) the classical one formed by the angiotensin converting enzyme (ACE), angiotensin (Ang) II and angiotensin type 1 (AT1) receptors; ii) the counter-regulatory arm consisting of ACE2, Ang-(1-7) and Mas receptor. Physical exercise can modulate this system, however, only animal studies have compared the effects of different intensity protocols on the RAS. No data with humans were provided. Therefore, we investigated the acute effect of two protocols of isowork aerobic exercise [High-Intensity Interval Exercise (HIIE) and Moderate-Intensity Continuous Exercise (MICE)] in plasma and urinary levels of RAS components in physically active men. MAIN METHODS The HIIE protocol included a 5-minute warm-up cycling at 60-70% of heart rate peak (HRp) intensity followed by 10 sets of 30 s above 90% with 1 min of recovery and 3 min of cool down. The MICE protocol was performed at a constant power corresponding to 60-70% of HRp and finalized at the same total work of HIIE. Blood and urine samples were collected before and after the protocols. Plasma and urinary levels of ACE, ACE2, Ang-(1-7) and Ang II were analyzed by enzyme-linked immunoassay. KEY FINDINGS While the HIIE protocol significantly increased urinary levels of ACE and plasma levels of ACE2, the MICE protocol elevated urinary concentrations of ACE2 and of Ang-(1-7). A greater increase of urine concentrations of Ang-(1-7) occurred in the MICE if compared with the HIIE protocol. SIGNIFICANCE Aerobic physical exercise acutely increases the activity of the counter-regulatory RAS axis, mostly the MICE protocol.
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Affiliation(s)
- Daniel Massote Magalhães
- Laboratório Interdisciplinar de Investigação Médica (LIIM), Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Av. Prof. Alfredo Balena, 190, Room 281, Belo Horizonte, Postal Code: 30130-100, MG, Brazil
| | - Albená Nunes-Silva
- Department of Physical Education and Sports, Centro Desportivo da Universidade Federal de Ouro Preto (UFOP), Rua Dois, 110, Campus Universitário - Ginásio de Esportes, Ouro Preto, MG, Postal Code: 35400-000, Brazil
| | - Guilherme Carvalho Rocha
- Laboratório Interdisciplinar de Investigação Médica (LIIM), Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Av. Prof. Alfredo Balena, 190, Room 281, Belo Horizonte, Postal Code: 30130-100, MG, Brazil
| | - Lucas Neves Vaz
- Laboratório Interdisciplinar de Investigação Médica (LIIM), Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Av. Prof. Alfredo Balena, 190, Room 281, Belo Horizonte, Postal Code: 30130-100, MG, Brazil
| | - Marcelo Henrique Salviano de Faria
- Laboratório Interdisciplinar de Investigação Médica (LIIM), Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Av. Prof. Alfredo Balena, 190, Room 281, Belo Horizonte, Postal Code: 30130-100, MG, Brazil
| | - Erica Leandro Marciano Vieira
- Laboratório Interdisciplinar de Investigação Médica (LIIM), Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Av. Prof. Alfredo Balena, 190, Room 281, Belo Horizonte, Postal Code: 30130-100, MG, Brazil
| | - Natalia Pessoa Rocha
- Laboratório Interdisciplinar de Investigação Médica (LIIM), Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Av. Prof. Alfredo Balena, 190, Room 281, Belo Horizonte, Postal Code: 30130-100, MG, Brazil
- Department of Neurology, University of Texas Health Science Center at Houston, USA
| | - Ana Cristina Simões e Silva
- Laboratório Interdisciplinar de Investigação Médica (LIIM), Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Av. Prof. Alfredo Balena, 190, Room 281, Belo Horizonte, Postal Code: 30130-100, MG, Brazil
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Belisário AR, Vieira ÉLM, de Almeida JA, Mendes FG, Miranda AS, Rezende PV, Viana MB, Simões e Silva AC. Evidence for interactions between inflammatory markers and renin-angiotensin system molecules in the occurrence of albuminuria in children with sickle cell anemia. Cytokine 2020; 125:154800. [DOI: 10.1016/j.cyto.2019.154800] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2018] [Revised: 04/29/2019] [Accepted: 08/05/2019] [Indexed: 12/12/2022]
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Li J, Zhao M, Jiang X, Liu T, Wang M, Zhao C. Synergistic therapeutic effects of Duzhong Jiangya Tablets and amlodipine besylate combination in spontaneously hypertensive rats using 1 H-NMR- and MS-based metabolomics. Biomed Chromatogr 2019; 34:e4741. [PMID: 31743479 DOI: 10.1002/bmc.4741] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/24/2019] [Revised: 11/06/2019] [Accepted: 11/06/2019] [Indexed: 01/09/2023]
Abstract
Duzhong Jiangya Tablet (DJT) composed of Eucommia ulmoides Oliv. and several other traditional Chinese medicines is a Chinese herbal compound, which is clinically used to treat hypertension. The aim of this study was to evaluate the antihypertensive effect of DJT and amlodipine besylate (AB) on the synergistic treatment of spontaneously hypertensive rats (SHRs), and to explore its antihypertensive mechanism. The synergistic therapeutic effect of DJT in combination with AB on SHR was studied using two metabolomics methods based on mass spectrum (MS) and nuclear magnetic resonance. Metabolomics analysis of plasma, urine, liver, and kidney and the combination of orthogonal partial least squares discriminant analysis was performed to expose potential biomarkers. Then, the overall metabolic characteristics and related abnormal metabolic pathways in hypertensive rats were constructed. Blood pressure measurements showed that DJT combined with AB has better effects in treating hypertension than it being alone. A total of 30 biomarkers were identified, indicating that hypertension disrupted the balance of multiple metabolic pathways in the body, and that combined administration restored metabolite levels better than their administration alone. The changes of biomarkers revealed the synergistic therapeutic mechanism of DJT combined with AB, which provided a reference for the combination of Chinese and Western medicines.
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Affiliation(s)
- Jingwei Li
- School of Pharmacy, Shenyang, Liaoning Province, China
| | - Min Zhao
- School of Pharmacy, Shenyang, Liaoning Province, China
| | - Xue Jiang
- School of Pharmacy, Shenyang, Liaoning Province, China
| | - Tingting Liu
- School of Pharmacy, Shenyang, Liaoning Province, China
| | - Miao Wang
- School of Life Science and Biopharmaceutics, Shenyang, Liaoning Province, China
| | - Chunjie Zhao
- School of Pharmacy, Shenyang, Liaoning Province, China
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25
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Huang YQ, Huang C, Zhang B, Feng YQ. Association of circulating miR-155 expression level and inflammatory markers with white coat hypertension. J Hum Hypertens 2019; 34:397-403. [PMID: 31481696 DOI: 10.1038/s41371-019-0250-7] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2019] [Revised: 06/17/2019] [Accepted: 06/28/2019] [Indexed: 01/07/2023]
Abstract
Circulating miR-155 play a vital role in hypertension. The aim of the present study was to explore the association of miR-155 with blood pressure and inflammatory markers, and to investigate the predictive value of circulating miR-155 for white coat hypertension (WCH). This cross-sectional study was continuously enrolled 105 subjects and was divided into three groups based on office blood pressure monitoring and 24-h ambulatory blood pressure monitoring (ABPM): normal hypertension, WCH, and hypertension group. Circulating miR-155 was assessed by quantitative real-time polymerase chain reaction (qRT-PCR). Spearman correlation coefficient and area under the ROC curve (AUC) were used. We found miR-155 in hypertension group were significantly higher than those in the WCH and normal hypertension group. The level of miR-155 was positively correlated with C-reactive protein, interleukin-6, office systolic blood pressure (SBP), and diastolic blood pressure (DBP), and ABMP parameters (24-h SBP, 24-h DBP, 24-h daytime SBP, 24-h daytime DBP, 24-h nighttime SBP and 24 h nighttime DBP) (all P < 0.05). Circulating miR-155 yielded an AUC of 0.843 (95% CI: 0.753, 0.933; P < 0.001) and 0.832 (95% CI: 0.736, 0.928; P < 0.001) for differing hypertension and WCH from control subjects, respectively. Our results suggested that miR-155 was significantly associated with inflammatory markers, and may become a potential noninvasive marker for WCH detection.
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Affiliation(s)
- Yu-Qing Huang
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, South China University of Technology School of Medicine, 510080, Guangzhou, China
| | - Cheng Huang
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, South China University of Technology School of Medicine, 510080, Guangzhou, China
| | - Bin Zhang
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, South China University of Technology School of Medicine, 510080, Guangzhou, China.
| | - Ying-Qing Feng
- Department of Cardiology, Guangdong Cardiovascular Institute, Guangdong Provincial Key Laboratory of Coronary Heart Disease Prevention, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, South China University of Technology School of Medicine, 510080, Guangzhou, China.
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26
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Rachid MA, da Silva Camargos ER, Marzano LAS, da Silva Oliveira B, Ferreira RN, Martinelli PM, Teixeira AL, Miranda AS, Simões E Silva AC. Effect of blockade of nitric oxide in heart tissue levels of Renin Angiotensin System components in acute experimental Chagas disease. Life Sci 2019; 219:336-342. [PMID: 30684542 DOI: 10.1016/j.lfs.2019.01.033] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2019] [Revised: 01/21/2019] [Accepted: 01/21/2019] [Indexed: 11/19/2022]
Abstract
Chagas disease (CD) is an important cause of cardiomyopathy in South America. The pathophysiology of CD is still a matter of debate. Renin Angiotensin System (RAS) components are clearly involved in cardiovascular diseases. RAS molecules interact with nitric oxide (NO) pathway in blood vessel and heart tissue. Thus, the aim of this study is to investigate possible changes in RAS molecules during the infection with Y strain T. cruzi and in response to acute administration of an inhibitor of the enzyme NO synthase, l-NAME. Male Holtzman rats were inoculated intraperitoneally with Y strain T. cruzi and received l-NAME or tap water from one day before the infection until 13 or 17 days post infection (dpi). Angiotensin converting enzyme 1 (ACE1) levels were significantly higher at day 17 when compared to baseline in atrium, whereas, in ventricle, ACE2 levels were significantly higher in 13 dpi when compared to baseline. In response to l-NAME treatment, atrium tissue levels of ACE1 were significantly reduced in treated animals at day 17, while Angiotensin-(1-7) concentration in atrium significantly increased in this group at the same time-point. No changes were detected in RAS components in the ventricle. ACE2 levels in Soleus muscle were significantly reduced in treated animals at day 13. In conclusion, changes in RAS molecules were detected during acute phase of T. cruzi infection and the inhibition of NO synthesis clearly interfered with expression of ACE1 and Angiotensin-(1-7) in the atrium.
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Affiliation(s)
- Milene Alvarenga Rachid
- Departamento de Patologia Geral, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Belo Horizonte, Minas Gerais, Brazil
| | | | | | - Bruna da Silva Oliveira
- Departamento de Morfologia, Instituto de Ciências Biológicas, UFMG, Belo Horizonte, Minas Gerais, Brazil
| | - Rodrigo Novaes Ferreira
- Departamento de Morfologia, Instituto de Ciências Biológicas, UFMG, Belo Horizonte, Minas Gerais, Brazil
| | | | - Antônio Lúcio Teixeira
- Neuropsychiatry Program, Department of Psychiatry & Behavioral Sciences, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX, USA
| | - Aline Silva Miranda
- Departamento de Morfologia, Instituto de Ciências Biológicas, UFMG, Belo Horizonte, Minas Gerais, Brazil; Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, UFMG, Belo Horizonte, Minas Gerais, Brazil.
| | - Ana Cristina Simões E Silva
- Laboratório Interdisciplinar de Investigação Médica, Faculdade de Medicina, UFMG, Belo Horizonte, Minas Gerais, Brazil
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27
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Changes in Renal Peritubular Capillaries in Canine and Feline Chronic Kidney Disease. J Comp Pathol 2018; 160:79-83. [DOI: 10.1016/j.jcpa.2018.03.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/07/2018] [Revised: 03/19/2018] [Accepted: 03/24/2018] [Indexed: 02/01/2023]
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Miranda A, Cordeiro T, dos Santos Lacerda Soares TM, Ferreira R, Simões e Silva A. Kidney–brain axis inflammatory cross-talk: from bench to bedside. Clin Sci (Lond) 2017; 131:1093-1105. [DOI: 10.1042/cs20160927] [Citation(s) in RCA: 48] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 08/30/2023]
Abstract
Epidemiologic data suggest that individuals at all stages of chronic kidney disease (CKD) have a higher risk of developing neuropsychiatric disorders, cognitive impairment, and dementia. This risk is generally explained by the high prevalence of both symptomatic and subclinical ischemic cerebrovascular lesions. However, other potential mechanisms, including cytokine/chemokine release, production of reactive oxygen species (ROS), circulating and local formation of trophic factors and of renin–angiotensin system (RAS) molecules, could also be involved, especially in the absence of obvious cerebrovascular disease. In this review, we discuss experimental and clinical evidence for the role of these mechanisms in kidney–brain cross-talk. In addition, we hypothesize potential pathways for the interactions between kidney and brain and their pathophysiological role in neuropsychiatric and cognitive changes found in patients with CKD. Understanding the pathophysiologic interactions between renal impairment and brain function is important in order to minimize the risk for future cognitive impairment and to develop new strategies for innovative pharmacological treatment.
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Affiliation(s)
- Aline Silva Miranda
- Laboratório de Neurobiologia, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Brazil
- Laboratório Interdisciplinar de Investigação Médica (LIIM), Faculdade de Medicina, UFMG, Belo Horizonte, Brazil
| | - Thiago Macedo Cordeiro
- Laboratório Interdisciplinar de Investigação Médica (LIIM), Faculdade de Medicina, UFMG, Belo Horizonte, Brazil
| | | | - Rodrigo Novaes Ferreira
- Laboratório de Neurobiologia, Departamento de Morfologia, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais (UFMG), Brazil
| | - Ana Cristina Simões e Silva
- Laboratório Interdisciplinar de Investigação Médica (LIIM), Faculdade de Medicina, UFMG, Belo Horizonte, Brazil
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Simões e Silva AC, Miranda AS, Rocha NP, Teixeira AL. Renin angiotensin system in liver diseases: Friend or foe? World J Gastroenterol 2017; 23:3396-3406. [PMID: 28596676 PMCID: PMC5442076 DOI: 10.3748/wjg.v23.i19.3396] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2017] [Revised: 03/17/2017] [Accepted: 04/12/2017] [Indexed: 02/06/2023] Open
Abstract
In the last three decades, the understanding of the renin angiotensin system (RAS) has been changed by the discoveries of functional local systems, novel biologically active peptides, additional specific receptors, alternative pathways of angiotensin (Ang) II generation, and new roles for enzymes and precursor components other than those in Ang II synthesis. In this regard, the discovery that Ang-(1-7) opposes the pressor, proliferative, pro-fibrotic, and pro-inflammatory effects mediated by Ang II has contributed to the realization that the RAS is composed of two axes. The first axis consists of the angiotensin-converting enzyme (ACE), with Ang II as the end product, and the angiotensin type 1 (AT1) receptor as the main effector mediating the biological actions of Ang II. The second axis results from ACE2-mediated hydrolysis of Ang II, leading to the production of Ang-(1-7), with the Mas receptor as the main effector conveying the vasodilatory, anti-proliferative, anti-fibrotic, and anti-inflammatory effects of Ang-(1-7). Experimental and clinical studies have shown that both axes of the RAS may take part in the pathogenesis of liver diseases. In this manuscript, we summarize the current evidence regarding the role of RAS in hepatic cirrhosis and its complications, including hemodynamic changes and hepatorenal syndrome. The therapeutic potential of the modulation of RAS molecules in liver diseases is also discussed.
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Transplantation of bone marrow-derived MSCs improves renal function and Na++K+-ATPase activity in rats with renovascular hypertension. Cell Tissue Res 2017; 369:287-301. [DOI: 10.1007/s00441-017-2602-3] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2016] [Accepted: 03/03/2017] [Indexed: 12/29/2022]
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Simões E Silva AC, Teixeira MM. ACE inhibition, ACE2 and angiotensin-(1-7) axis in kidney and cardiac inflammation and fibrosis. Pharmacol Res 2016; 107:154-162. [PMID: 26995300 DOI: 10.1016/j.phrs.2016.03.018] [Citation(s) in RCA: 168] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/30/2015] [Revised: 03/03/2016] [Accepted: 03/14/2016] [Indexed: 12/21/2022]
Abstract
The Renin Angiotensin System (RAS) is a pivotal physiological regulator of heart and kidney homeostasis, but also plays an important role in the pathophysiology of heart and kidney diseases. Recently, new components of the RAS have been discovered, including angiotensin converting enzyme 2 (ACE2), Angiotensin(Ang)-(1-7), Mas receptor, Ang-(1-9) and Alamandine. These new components of RAS are formed by the hydrolysis of Ang I and Ang II and, in general, counteract the effects of Ang II. In experimental models of heart and renal diseases, Ang-(1-7), Ang-(1-9) and Alamandine produced vasodilation, inhibition of cell growth, anti-thrombotic, anti-inflammatory and anti-fibrotic effects. Recent pharmacological strategies have been proposed to potentiate the effects or to enhance the formation of Ang-(1-7) and Ang-(1-9), including ACE2 activators, Ang-(1-7) in hydroxypropyl β-cyclodextrin, cyclized form of Ang-(1-7) and nonpeptide synthetic Mas receptor agonists. Here, we review the role and effects of ACE2, ACE2 activators, Ang-(1-7) and synthetic Mas receptor agonists in the control of inflammation and fibrosis in cardiovascular and renal diseases and as counter-regulators of the ACE-Ang II-AT1 axis. We briefly comment on the therapeutic potential of the novel members of RAS, Ang-(1-9) and alamandine, and the interactions between classical RAS inhibitors and new players in heart and kidney diseases.
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Affiliation(s)
- Ana Cristina Simões E Silva
- Laboratório Interdisciplinar de Investigação Médica, Unidade de Nefrologia Pediátrica, Faculdade de Medicina, Universidade Federal de Minas Gerais (UFMG), Brazil.
| | - Mauro Martins Teixeira
- Laboratório de Imunofarmacologia, Departamento de Bioquímica e Imunologia, ICB, UFMG, Brazil
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32
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Gastrodin Reduces Blood Pressure by Intervening with RAAS and PPARγ in SHRs. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE 2015; 2015:828427. [PMID: 26587048 PMCID: PMC4637485 DOI: 10.1155/2015/828427] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2015] [Revised: 07/15/2015] [Accepted: 10/11/2015] [Indexed: 01/13/2023]
Abstract
Gastrodin is a bioactive compound extracted from traditional Chinese medicine, Gastrodia elata Bl. It has a definite effect on reducing blood pressure in hypertensive patients. However, the mechanisms of gastrodin in lowering blood pressure still remain unclear. In this study, 4 weeks of administration of gastrodin (100 mg/kg/d intraperitoneally injected) decreased the systolic blood pressure (SBP) in spontaneously hypertensive rats (SHRs) (190.2 ± 8.9 versus 169.8 ± 6.4, P < 0.01). Among SHRs receiving gastrodin treatment, angiotensin II (Ang II) and aldosterone (ALD) in serum were significantly decreased (2022.1 ± 53.0 versus 1528.7 ± 93.9, 213.33 ± 35.17 versus 179.65 ± 20.31, and P < 0.01, P < 0.05, resp.) and dramatically downregulated expression of angiotensin type 1 receptor (AT1R) (4.9 ± 0.9 versus 2.6 ± 0.9, P < 0.05) in myocardium in both mRNA and protein levels compared with their corresponding groups without gastrodin treatment. Additionally, gastrodin increased the mRNA expression (0.18 ± 0.07 versus 0.82 ± 0.10, P < 0.01) and protein synthesis (0.40 ± 0.10 versus 0.34 ± 0.10, P < 0.01) of peroxisome proliferator-activated receptor γ (PPARγ) in myocardium tissues. Overall, our data demonstrated that gastrodin was able to decrease the SBP in SHR. Furthermore, this study showed that gastrodin intervened with the renin-angiotensin-aldosterone system (RAAS) and PPARγ effectively, which indicates its antihypertensive mechanism.
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Mahler B, Kamperis K, Ankarberg-Lindgren C, Djurhuus JC, Rittig S. The effect of puberty on diurnal sodium regulation. Am J Physiol Renal Physiol 2015; 309:F873-9. [PMID: 26336163 DOI: 10.1152/ajprenal.00319.2014] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2014] [Accepted: 08/26/2015] [Indexed: 11/22/2022] Open
Abstract
The aim of this study was to investigate the impact of sex and puberty stage on circadian changes in sodium excretion, sodium-regulating hormones, and hemodynamics. Thirty-nine healthy volunteers (9 prepuberty boys, 10 prepuberty girls, 10 puberty boys, and 10 puberty girls) were included. They all underwent a 24-h circadian in-patient study under standardized conditions regarding activity, diet, and fluid intake. Blood samples were drawn every 4 h, and the urine was collected in fractions. Blood pressure and heart rate were noninvasively monitored. Atrial natriuretic peptide (ANP), angiotensin II, aldosterone, and renin were measured in blood. Children in puberty had lower plasma levels of renin (P<0.05) and angiotensin II (P<0.05) and a 26% reduction in filtered sodium without changes in sodium excretion compared with prepuberty children. A circadian rhythm in sodium excretion, the renin-angiotensin system, ANP, and blood pressure was found with a midnight ANP peak (P<0.001), a nighttime decrease in hemodynamic parameters (P<0.001), an increase in plasma renin (P<0.001) and angiotensin II (P<0.001), and a decrease in sodium excretion (P<0.001) mainly on the basis of increased sodium reabsorption (P<0.001). The timing of the changes did not depend on sex or puberty group. There is a circadian rhythm of sodium excretion and sodium regulation in 7- to 15-yr-old children. This rhythm is similar in boys and girls. As an important new finding, puberty changes the plasma levels of renin and angiotensin II without changing the amount of sodium excreted or the day to night sodium excretion ratio.
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Affiliation(s)
- B Mahler
- Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark;
| | - K Kamperis
- Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark
| | | | - J C Djurhuus
- The Institute of Clinical Medicine, Aarhus University Hospital, Aarhus, Denmark
| | - S Rittig
- Department of Pediatrics, Aarhus University Hospital, Aarhus, Denmark
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dos Santos Junior ACS, de Miranda DM, Simões e Silva AC. Congenital anomalies of the kidney and urinary tract: An embryogenetic review. ACTA ACUST UNITED AC 2014; 102:374-81. [DOI: 10.1002/bdrc.21084] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/25/2014] [Accepted: 10/27/2014] [Indexed: 11/10/2022]
Affiliation(s)
| | - Debora Marques de Miranda
- National Institute of Science and Technology-Molecular Medicine (INCT-MM), Universidade Federal de Minas Gerais (UFMG); Brazil
- Faculty of Medicine; Department of Pediatrics; Unit of Pediatric Nephrology; Pediatric Branch of the Interdisciplinary Laboratory of Medical Investigation, UFMG; Brazil
| | - Ana Cristina Simões e Silva
- National Institute of Science and Technology-Molecular Medicine (INCT-MM), Universidade Federal de Minas Gerais (UFMG); Brazil
- Faculty of Medicine; Department of Pediatrics; Unit of Pediatric Nephrology; Pediatric Branch of the Interdisciplinary Laboratory of Medical Investigation, UFMG; Brazil
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35
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Nadeem S, Batisky DL. Aliskiren, the first direct renin inhibitor: assessing a role in pediatric hypertension and kidney diseases. Pediatr Nephrol 2014; 29:2105-11. [PMID: 24337365 PMCID: PMC4057986 DOI: 10.1007/s00467-013-2716-0] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/28/2013] [Revised: 11/20/2013] [Accepted: 11/20/2013] [Indexed: 01/01/2023]
Abstract
This article provides a review of the role of aliskiren, a direct renin inhibitor, in pediatric hypertension and kidney diseases. Among the many mechanisms involved in regulating blood pressure, the renin-angiotensin-aldosterone system (RAAS) plays a major role. Additionally, the RAAS has been identified as a contributing factor to cardiovascular and renal diseases for more than three decades. The potential benefits of inhibiting the RAAS by aliskiren alone or in combination with other RAAS blockers (ACEIs, ARBs) seem to be theoretically promising. However, caution should be exercised in treating children, especially in those with significant chronic kidney disease until there is more evidence regarding the safety and efficacy of this new drug in the pediatric population from ongoing clinical trials.
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36
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Miranda DM, dos Santos AC, Sarubi HC, Bastos-Rodrigues L, Rosa DV, Freitas IS, De Marco LA, Oliveira EA, Simões e Silva AC. Association of angiotensin type 2 receptor gene polymorphisms with ureteropelvic junction obstruction in Brazilian patients. Nephrology (Carlton) 2014; 19:714-20. [DOI: 10.1111/nep.12308] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 06/23/2014] [Indexed: 11/29/2022]
Affiliation(s)
- Debora M Miranda
- INCT/MM - National Institute of Science and Technology in Molecular Medicine; Federal University of Minas Gerais (UFMG); Belo Horizonte Brazil
- Department of Pediatrics, Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Unity of Pediatric Nephrology; Federal University of Minas Gerais (UFMG); Belo Horizonte Brazil
| | - Augusto Cesar dos Santos
- INCT/MM - National Institute of Science and Technology in Molecular Medicine; Federal University of Minas Gerais (UFMG); Belo Horizonte Brazil
- Department of Pediatrics, Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Unity of Pediatric Nephrology; Federal University of Minas Gerais (UFMG); Belo Horizonte Brazil
| | - Helena C Sarubi
- INCT/MM - National Institute of Science and Technology in Molecular Medicine; Federal University of Minas Gerais (UFMG); Belo Horizonte Brazil
| | - Luciana Bastos-Rodrigues
- INCT/MM - National Institute of Science and Technology in Molecular Medicine; Federal University of Minas Gerais (UFMG); Belo Horizonte Brazil
| | - Daniela Valadão Rosa
- INCT/MM - National Institute of Science and Technology in Molecular Medicine; Federal University of Minas Gerais (UFMG); Belo Horizonte Brazil
| | - Izabella S Freitas
- INCT/MM - National Institute of Science and Technology in Molecular Medicine; Federal University of Minas Gerais (UFMG); Belo Horizonte Brazil
| | - Luiz Armando De Marco
- INCT/MM - National Institute of Science and Technology in Molecular Medicine; Federal University of Minas Gerais (UFMG); Belo Horizonte Brazil
| | - Eduardo A Oliveira
- INCT/MM - National Institute of Science and Technology in Molecular Medicine; Federal University of Minas Gerais (UFMG); Belo Horizonte Brazil
- Department of Pediatrics, Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Unity of Pediatric Nephrology; Federal University of Minas Gerais (UFMG); Belo Horizonte Brazil
| | - Ana Cristina Simões e Silva
- INCT/MM - National Institute of Science and Technology in Molecular Medicine; Federal University of Minas Gerais (UFMG); Belo Horizonte Brazil
- Department of Pediatrics, Interdisciplinary Laboratory of Medical Investigation, Faculty of Medicine, Unity of Pediatric Nephrology; Federal University of Minas Gerais (UFMG); Belo Horizonte Brazil
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Simões e Silva AC, Silveira KD, Ferreira AJ, Teixeira MM. ACE2, angiotensin-(1-7) and Mas receptor axis in inflammation and fibrosis. Br J Pharmacol 2014; 169:477-92. [PMID: 23488800 DOI: 10.1111/bph.12159] [Citation(s) in RCA: 415] [Impact Index Per Article: 37.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2012] [Revised: 02/04/2013] [Accepted: 02/13/2013] [Indexed: 12/14/2022] Open
Abstract
Recent advances have improved our understanding of the renin-angiotensin system (RAS). These have included the recognition that angiotensin (Ang)-(1-7) is a biologically active product of the RAS cascade. The identification of the ACE homologue ACE2, which forms Ang-(1-7) from Ang II, and the GPCR Mas as an Ang-(1-7) receptor have provided the necessary biochemical and molecular background and tools to study the biological significance of Ang-(1-7). Most available evidence supports a counter-regulatory role for Ang-(1-7) by opposing many actions of Ang II on AT₁ receptors, especially vasoconstriction and proliferation. Many studies have now shown that Ang-(1-7) by acting via Mas receptor exerts inhibitory effects on inflammation and on vascular and cellular growth mechanisms. Ang-(1-7) has also been shown to reduce key signalling pathways and molecules thought to be relevant for fibrogenesis. Here, we review recent findings related to the function of the ACE2/Ang-(1-7)/Mas axis and focus on the role of this axis in modifying processes associated with acute and chronic inflammation, including leukocyte influx, fibrogenesis and proliferation of certain cell types. More attention will be given to the involvement of the ACE2/Ang-(1-7)/Mas axis in the context of renal disease because of the known relevance of the RAS for the function of this organ and for the regulation of kidney inflammation and fibrosis. Taken together, this knowledge may help in paving the way for the development of novel treatments for chronic inflammatory and renal diseases.
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Affiliation(s)
- A C Simões e Silva
- Departamento de Pediatria, Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Brazil
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Deng H, Zheng J, Zhang F, Wang Y, Kan J. Isolation of angiotensin I-converting enzyme inhibitor from pepsin hydrolysate of porcine hemoglobin. Eur Food Res Technol 2014. [DOI: 10.1007/s00217-014-2290-0] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/24/2022]
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Drapala A, Sikora M, Ufnal M. Statins, the renin–angiotensin–aldosterone system and hypertension – a tale of another beneficial effect of statins. J Renin Angiotensin Aldosterone Syst 2014; 15:250-8. [DOI: 10.1177/1470320314531058] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Affiliation(s)
- Adrian Drapala
- Department of Experimental and Clinical Physiology, Medical University of Warsaw, Poland
| | - Mariusz Sikora
- Department of Experimental and Clinical Physiology, Medical University of Warsaw, Poland
| | - Marcin Ufnal
- Department of Experimental and Clinical Physiology, Medical University of Warsaw, Poland
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Sayed M, Drummond CA, Evans KL, Haller ST, Liu J, Xie Z, Tian J. Effects of Na/K-ATPase and its ligands on bone marrow stromal cell differentiation. Stem Cell Res 2014; 13:12-23. [PMID: 24793006 DOI: 10.1016/j.scr.2014.04.002] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/23/2013] [Revised: 03/21/2014] [Accepted: 04/05/2014] [Indexed: 12/16/2022] Open
Abstract
Endogenous ligands of Na/K-ATPase have been demonstrated to increase in kidney dysfunction and heart failure. It is also reported that Na/K-ATPase signaling function effects stem cell differentiation. This study evaluated whether Na/K-ATPase activation through its ligands and associated signaling functions affect bone marrow stromal cells (BMSCs, also known as bone marrow-derived mesenchymal stem cells) differentiation capacity. BMSCs were isolated from male Sprague-Dawley rats and cultured in minimal essential medium alpha (MEM-α) supplemented with 15% Fetal Bovine serum (FBS). The results showed that marinobufagenin (MBG), a specific Na/K-ATPase ligand, potentiated rosiglitazone-induced adipogenesis in these BMSCs. Meanwhile, it attenuated BMSC osteogenesis. Mechanistically, MBG increased CCAAT/enhancer binding protein alpha (C/EBPα) protein expression through activation of an extracellular regulated kinase (ERK) signaling pathway, which leads to enhanced rosiglitazone-induced adipogenesis. Inhibition of ERK activation by U0126 blocks the effect of MBG on C/EBPα expression and on rosiglitazone-induced adipogenesis. Reciprocally, MBG reduced runt-related transcription factor 2 (RunX2) expression, which resulted in the inhibition of osteogenesis induced by β-glycerophosphate/ascorbic acid. MBG also potentiated rosiglitazone-induced adipogenesis in 3T3-L1 cells and in mouse BMSCs. These results suggest that Na/K-ATPase and its signaling functions are involved in the regulation of BMSCs differentiation.
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Affiliation(s)
- Moustafa Sayed
- Department of Medicine, University of Toledo, Toledo, OH, USA
| | | | - Kaleigh L Evans
- Department of Medicine, University of Toledo, Toledo, OH, USA
| | - Steven T Haller
- Department of Medicine, University of Toledo, Toledo, OH, USA
| | - Jiang Liu
- Joan C. Edwards School of Medicine, Marshall University, Huntington, WV, USA
| | - Zijian Xie
- Department of Medicine, University of Toledo, Toledo, OH, USA
| | - Jiang Tian
- Department of Medicine, University of Toledo, Toledo, OH, USA.
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Richards J, Cheng KY, All S, Skopis G, Jeffers L, Lynch IJ, Wingo CS, Gumz ML. A role for the circadian clock protein Per1 in the regulation of aldosterone levels and renal Na+ retention. Am J Physiol Renal Physiol 2013; 305:F1697-704. [PMID: 24154698 DOI: 10.1152/ajprenal.00472.2013] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The circadian clock plays an important role in the regulation of physiological processes, including renal function and blood pressure. We have previously shown that the circadian protein period (Per)1 regulates the expression of multiple Na(+) transport genes in the collecting duct, including the α-subunit of the renal epithelial Na(+) channel. Consistent with this finding, Per1 knockout mice exhibit dramatically lower blood pressure than wild-type mice. We have also recently demonstrated the potential opposing actions of cryptochrome (Cry)2 on Per1 target genes. Recent work by others has demonstrated that Cry1/2 regulates aldosterone production through increased expression of the adrenal gland-specific rate-limiting enzyme 3β-dehydrogenase isomerase (3β-HSD). Therefore, we tested the hypothesis that Per1 plays a role in the regulation of aldosterone levels and renal Na(+) retention. Using RNA silencing and pharmacological blockade of Per1 nuclear entry in the NCI-H295R human adrenal cell line, we showed that Per1 regulates 3β-HSD expression in vitro. These results were confirmed in vivo: mice with reduced levels of Per1 had decreased levels of plasma aldosterone and decreased mRNA expression of 3β-HSD. We postulated that mice with reduced Per1 would have a renal Na(+)-retaining defect. Indeed, metabolic cage experiments demonstrated that Per1 heterozygotes excreted more urinary Na(+) compared with wild-type mice. Taken together, these data support the hypothesis that Per1 regulates aldosterone levels and that Per1 plays an integral role in the regulation of Na(+) retention.
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Mitani S, Yabuki A, Sawa M, Chang HS, Yamato O. Intrarenal distributions and changes of Angiotensin-converting enzyme and Angiotensin-converting enzyme 2 in feline and canine chronic kidney disease. J Vet Med Sci 2013; 76:45-50. [PMID: 24004970 PMCID: PMC3979943 DOI: 10.1292/jvms.13-0314] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023] Open
Abstract
Angiotensin-converting enzyme (ACE) is a key enzyme in the renin-angiotensin
system (RAS). ACE2 is a newly identified member of the RAS. The present
immunohistochemical study focused on changes in intrarenal ACE and ACE2 immunoreactivity
in feline and canine chronic kidney disease (CKD). ACE immunoreactivity was predominantly
observed in the brush border of the proximal tubules in dogs and cats. ACE
immunoreactivity was lower in CKD kidneys than in normal kidneys, and quantitative
analysis demonstrated negative correlations between ACE and renal tissue damage in dogs.
ACE2 immunoreactivity was also detected in the proximal tubules; it increased or decreased
with CKD in dogs, depending on the renal region assessed. The changes in ACE and ACE2 in
CKD were associated with the plasma creatinine concentration in dogs. Findings from dogs
with glomerulonephritis were similar to those from dogs with non-glomerulonephritis. The
present study suggests that changes in the intrarenal expression of ACE and ACE2
contribute to the pathological mechanisms of canine CKD, but not to the mechanisms of
feline CKD.
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Affiliation(s)
- Sawane Mitani
- Laboratory of Veterinary Clinical Pathology, Joint Faculty of Veterinary Medicine, Kagoshima University, 1-21-24 Korimoto, Kagoshima 890-0065, Japan
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Morais HA, Silvestre MP, Amorin LL, Silva VD, Silva MR, Simões e Silva AC, Silveira JN. Use of Different Proteases to Obtain Whey Protein Concentrate Hydrolysates with Inhibitory Activity toward Angiotensin-Converting Enzyme. J Food Biochem 2013. [DOI: 10.1111/jfbc.12032] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022]
Affiliation(s)
- Harriman A. Morais
- Federal University of Jequitinhonha and Mucuri Valleys (UFVJM); Diamantina MG Brazil
- Federal University of Minas Gerais (UFMG); Avenida Pres. Antônio Carlos, 6627 31270-901 Belo Horizonte MG Brazil
| | - Marialice P.C. Silvestre
- Federal University of Minas Gerais (UFMG); Avenida Pres. Antônio Carlos, 6627 31270-901 Belo Horizonte MG Brazil
- EDETEC Food Industry S.A.; Avenida José Cândido da Silveira, 2100, sala 24 31035-536 Belo Horizonte MG Brazil
| | - Larissa L. Amorin
- Federal University of Minas Gerais (UFMG); Avenida Pres. Antônio Carlos, 6627 31270-901 Belo Horizonte MG Brazil
| | - Viviane D.M. Silva
- EDETEC Food Industry S.A.; Avenida José Cândido da Silveira, 2100, sala 24 31035-536 Belo Horizonte MG Brazil
| | - Mauro R. Silva
- Federal University of Minas Gerais (UFMG); Avenida Pres. Antônio Carlos, 6627 31270-901 Belo Horizonte MG Brazil
- EDETEC Food Industry S.A.; Avenida José Cândido da Silveira, 2100, sala 24 31035-536 Belo Horizonte MG Brazil
| | - Ana Cristina Simões e Silva
- Federal University of Minas Gerais (UFMG); Avenida Pres. Antônio Carlos, 6627 31270-901 Belo Horizonte MG Brazil
| | - Josianne N. Silveira
- Federal University of Minas Gerais (UFMG); Avenida Pres. Antônio Carlos, 6627 31270-901 Belo Horizonte MG Brazil
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Liu Y, Liang W, Yang Q, Ren Z, Chen X, Zha D, Singhal PC, Ding G. IQGAP1 mediates angiotensin II-induced apoptosis of podocytes via the ERK1/2 MAPK signaling pathway. Am J Nephrol 2013; 38:430-44. [PMID: 24247724 DOI: 10.1159/000355970] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2013] [Accepted: 09/23/2013] [Indexed: 01/20/2023]
Abstract
BACKGROUND/AIMS The mechanism underlying angiotensin II (AngII)-promoted podocyte apoptosis has not been established. IQ domain GTPase-activating protein 1 (IQGAP1) is a scaffolding protein of the mitogen-activated protein kinases (MAPK) signaling pathway, and plays a significant role in apoptosis. The present study evaluates the role of IQGAP1 in AngII-induced podocyte apoptosis. METHODS We randomly assigned 36 male Wistar rats to a normal saline-infused group, an AngII-infused group, or a normal control group, and measured podocyte apoptosis by the terminal deoxynucleotidyl transferase-mediated dUTP-biotin nick end labeling (TUNEL) assay and transmission electron microscopic analysis. In addition, we exposed differentiated mouse podocytes to AngII and then assessed apoptosis by flow cytometry and Hoechst-33258 staining. Expression of IQGAP1 was measured by Western blotting, real-time PCR and immunofluorescence assay in vivo and in vitro. IQGAP1 siRNA and MAPK pathway inhibitors were further introduced to investigate the role of IQGAP1 and MAPK signaling in the process. Coimmunoprecipitation was used to evaluate the interaction between ERK1/2 and IQGAP1. RESULTS AngII promoted podocyte apoptosis in vivo and in vitro. IQGAP1 had a linear distribution along the capillary loops of glomeruli in vivo, and was in the cellular membrane and cytoplasm of cultured podocytes. AngII stimulated IQGAP1 expression and increased phosphorylation of P38, JNK, and ERK1/2. Knockdown of IQGAP1 with siRNA prevented AngII-induced apoptosis of podocytes and reduced AngII-induced phosphorylation of ERK1/2, but not that of P38, JNK. This was accompanied by a reduced interaction between ERK1/2 and IQGAP1. CONCLUSION IQGAP1 contributes to AngII-induced apoptosis of podocytes by interacting with the ERK1/2 signaling protein.
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Affiliation(s)
- Yipeng Liu
- Division of Nephrology, Renmin Hospital of Wuhan University, Wuhan, China
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Silvestre MPC, Silva MR, Silva VDM, Souza MWSD, Lopes Junior CDO, Afonso WDO. Analysis of whey protein hydrolysates: peptide profile and ACE inhibitory activity. BRAZ J PHARM SCI 2012. [DOI: 10.1590/s1984-82502012000400019] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022] Open
Abstract
The aim of this study was to prepare enzymatic hydrolysates from whey protein concentrate with a nutritionally adequate peptide profile and the ability to inhibit angiotensin-converting enzyme (ACE) activity. The effects of the type of enzyme used (pancreatin or papain), the enzyme:substrate ratio (E:S ratio=0.5:100, 1:100, 2:100 and 3:100) and the use of ultrafiltration (UF) were investigated. The fractionation of peptides was performed by size-exclusion-HPLC, and the quantification of the components of the chromatographic fractions was carried out by a rapid Corrected Fraction Area method. The ACE inhibitory activity (ACE-IA) was determined by Reverse Phase-HPLC. All parameters tested affected both the peptide profile and the ACE-IA. The best peptide profile was achieved for the hydrolysates obtained with papain, whereas pancreatin was more advantageous in terms of ACE-IA. The beneficial effect of using a lower E:S ratio on the peptide profile and ACE-IA was observed for both enzymes depending on the conditions used to prepare the hydrolysates. The beneficial effect of not using UF on the peptide profile was observed in some cases for pancreatin and papain. However, the absence of UF yielded greater ACE-IA only when using papain.
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Kukkar A, Singh N, Jaggi AS. Neuropathic pain-attenuating potential of aliskiren in chronic constriction injury model in rats. J Renin Angiotensin Aldosterone Syst 2012; 14:116-23. [PMID: 23087256 DOI: 10.1177/1470320312460899] [Citation(s) in RCA: 23] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
The present study was designed to investigate the potential of aliskiren, a direct renin inhibitor, in chronic constriction injury (CCI)-induced neuropathic pain in rats. Neuropathic pain was induced by placing four loose ligatures around the sciatic nerve. Acetone drop, von Frey hair, pin-prick and hot plate tests were performed to assess cold allodynia, mechanical allodynia, mechanical and heat hyperalgesia, respectively. The levels of Tumor necrosis factor-alpha (TNF-α) were measured in the sciatic nerve as an inflammatory marker. CCI was associated with the development of cold allodynia, mechanical allodynia, mechanical and heat hyperalgesia along with a rise in the levels of Tumor necrosis factor-alpha (TNF-α). Administration of aliskiren (25 or 50 mg/kg intraperitoneal (i.p.)) for 14 days in CCI-subjected rats significantly attenuated CCI-induced pain-related behavior and rise in TNF-α level. It may be concluded that aliskiren-mediated anti-inflammatory actions may be responsible for its beneficial effects in neuropathic pain in rats.
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Affiliation(s)
- Ankesh Kukkar
- Department of Pharmaceutical Sciences and Drug Research, Punjabi University, India
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Labonté ME, Dewailly E, Chateau-Degat ML, Couture P, Lamarche B. Population-based study of high plasma C-reactive protein concentrations among the Inuit of Nunavik. Int J Circumpolar Health 2012; 71:19066. [PMID: 23087913 PMCID: PMC3475996 DOI: 10.3402/ijch.v71i0.19066] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2012] [Revised: 09/17/2012] [Accepted: 09/19/2012] [Indexed: 01/08/2023] Open
Abstract
Background The shift away from traditional lifestyle in the Inuit population over the past few decades has been associated with an increased prevalence of coronary heart disease (CHD) risk factors such as obesity, high blood pressure (BP) and diabetes. However, the impact of this transition on the pro-inflammatory marker high-sensitivity C-reactive protein (hs-CRP) has not been documented. Objectives To examine the prevalence of elevated plasma hs-CRP concentrations in Inuit from Nunavik in the province of Quebec (Canada) and identify anthropometric, biochemical and lifestyle risk factors associated with elevated hs-CRP. Design A population-representative sample of 801 Inuit residents from 14 villages of Nunavik, aged between 18 and 74 years, was included in the analyses. Subjects participated in a clinical session and completed questionnaires on lifestyle. Multivariate logistic regression was used to determine risk factors for elevated hs-CRP. Results Elevated plasma hs-CRP concentrations (≥2 mg/L) were present in 32.7% (95% confidence interval (CI) 29.5–35.8) of the Inuit adult population and were more prevalent among women than among men (36.7% vs. 29.0%, p=0.007). Multivariate logistic regression analysis indicated that every 1 mmHg increase in systolic BP was associated with a 3% increase in the odds of having hs-CRP concentrations ≥2 mg/L in the Inuit population (95% CI 1.01–1.04). The combination of older age (≥50 vs. <30 years) and elevated waist circumference (gender-specific cut-off values) in a multivariate logistic model was also associated with a 13.3-fold increase in the odds of having plasma hs-CRP concentrations ≥2 mg/L (95% CI 5.8–30.9). Conclusions These data indicate that elevated hs-CRP is relatively prevalent among Inuit with values that are similar to those seen in Canadian Caucasian populations. Sex, age, waist circumference and systolic BP are major factors that increase the risk of this inflammatory phenotype among Inuit from Nunavik, despite their different lifestyle background compared with Caucasians.
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Affiliation(s)
- Marie-Eve Labonté
- Institute of Nutraceuticals and Functional Foods, Laval University, Québec, QC, Canada
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Abstract
Much attention recently has been focused on stem cell technology as a possible alternative modality of treatment of a variety of diseases. Chronic kidney disease is a serious health problem and most chronic kidney diseases share in common the presence of interstitial and glomerular fibrosis, regardless of the underlying cause. To date there are no specific therapies aimed at treating fibrosis in the kidney. In a novel effort to address the underlying pathology in kidney disease, researchers are demonstrating that stem cell therapy can attenuate fibrosis in chronic kidney disease in animal models. This review will focus on the recent developments in stem cell research and their possible implications to treat chronic kidney disease.
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Li XM, Ling Y, Lu DR, Lu ZQ, Liu Y, Chen HY, Gao X. The obesity-related polymorphism PCSK1 rs6235 is associated with essential hypertension in the Han Chinese population. Hypertens Res 2012; 35:994-9. [PMID: 22592666 DOI: 10.1038/hr.2012.79] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Proprotein convertase subtilisin/kexin-type 1 (PCSK1) is a prohormone convertase that has an important role in prohormone maturation including the process of prorenin to renin. We studied the association of the PCSK1 single-nucleotide polymorphism (SNP) rs6235 (encoding an S690T substitution) with essential hypertension (EH), obesity and related traits in the Han Chinese population. The rs6235 SNP in the PCSK1 gene was investigated using a case-control study design, with 1034 hypertension cases and 1112 normotensive controls. In this study, the rs6235 SNP was significantly associated with hypertension (OR=1.26, 95% CI (1.10-1.46), P=0.001); the odds ratios of GC vs GG and CC vs GG were 1.30 (95% CI (1.06-1.58), P=0.010) and 1.55 (95% CI (1.12-2.13), P=0.007), respectively. In the controls, the C-allele was associated with increased systolic (P=0.010) and diastolic (P=0.010) blood pressure levels. In all of the EH patients and EH patients without a history of renin-angiotensin-aldosterone (RAA) system-related antagonists, the C-allele was associated with increased plasma renin activity (P=0.00004 and 0.002, respectively) and aldosterone levels (P=0.018 and 0.005, respectively). The C-allele was also associated with increased body mass index (BMI) (P=0.010) in the normotensive controls. In conclusion, the PCSK1 SNP rs6235 was associated with EH and blood pressure in the Han Chinese population, and this association may be mediated by the SNP's effect on RAA levels. rs6235 was also associated with BMI in this population.
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Affiliation(s)
- Xiao-Mu Li
- Department of Endocrinology and Metabolism, Zhongshan Hospital, Fudan University, Shanghai, China
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