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Zeicu C, Fisk M, Evans NR. Investigating secondary hypertension in cerebrovascular disease. Pract Neurol 2025; 25:143-149. [PMID: 39317448 DOI: 10.1136/pn-2024-004169] [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] [Accepted: 08/25/2024] [Indexed: 09/26/2024]
Abstract
Hypertension is the leading cause of stroke in the UK and worldwide. In recent years, stroke incidence has increased by 30%-41.5% in people aged under 64 years, with the prevalence of hypertension increasing by 4%-11%. Given that 5%-10% of people with hypertension in the general population have an underlying cause for their elevated blood pressure, it is important that all clinicians should maintain a high clinical suspicion for secondary hypertension. This review provides a clinical perspective of when to consider the underlying causes of secondary hypertension, with investigation algorithms for patients presenting with stroke and hypertension. Early involvement of hypertension specialist services is important to identify secondary causes of hypertension, as its effective control reduces cardiovascular-associated morbidity.
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Affiliation(s)
- Claudia Zeicu
- Department of Stroke Medicine, Cambridge University Hospitals NHS Foundation Trust, Cambridge, UK
| | - Marie Fisk
- Department of Clinical Pharmacology, University of Cambridge, Cambridge, UK
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2
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Teo LTK, Juantuah-Kusi N, Subramanian G, Sampath P. Psoriasis Treatments: Emerging Roles and Future Prospects of MicroRNAs. Noncoding RNA 2025; 11:16. [PMID: 39997616 PMCID: PMC11858470 DOI: 10.3390/ncrna11010016] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2024] [Revised: 01/22/2025] [Accepted: 02/04/2025] [Indexed: 02/26/2025] Open
Abstract
Psoriasis, a widespread and chronic inflammatory skin disorder, is marked by its persistence and the lack of a definitive cure. The pathogenesis of psoriasis is increasingly understood, with ongoing research highlighting the intricate interplay of genetic, immunological, and environmental factors. Recent advancements have illuminated the pivotal role of microRNAs in orchestrating complex processes in psoriasis and other hyperproliferative skin diseases. This narrative review highlights the emerging significance of miRNAs as key regulators in psoriasis pathogenesis and examines their potential as therapeutic targets. We discuss current treatment approaches and the promising future of miRNAs as next-generation therapeutic agents for this condition.
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Affiliation(s)
- Li Tian Keane Teo
- Department of Life Sciences, Imperial College London, Sir Ernst Chain Building, South Kensington, London SW7 2AZ, UK
| | - Nerissa Juantuah-Kusi
- Division of Biomedical Sciences, Warwick Medical School, University of Warwick, Coventry CV4 7AL, UK
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), 8A Biomedical Grove #06-06 Immunos, Singapore 138648, Singapore
| | - Gowtham Subramanian
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), 8A Biomedical Grove #06-06 Immunos, Singapore 138648, Singapore
- Skin Research Institute of Singapore (SRIS), 11 Mandalay Road #17-01 Clinical Sciences Building, Singapore 308232, Singapore
| | - Prabha Sampath
- A*STAR Skin Research Labs (A*SRL), Agency for Science, Technology, and Research (A*STAR), 8A Biomedical Grove #06-06 Immunos, Singapore 138648, Singapore
- Skin Research Institute of Singapore (SRIS), 11 Mandalay Road #17-01 Clinical Sciences Building, Singapore 308232, Singapore
- Program in Cancer and Stem Cell Biology, Duke-NUS Medical School 8 College Road, Singapore 169857, Singapore
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3
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Evans LC, Dayton A, Osborn JW. Renal nerves in physiology, pathophysiology and interoception. Nat Rev Nephrol 2025; 21:57-69. [PMID: 39363020 DOI: 10.1038/s41581-024-00893-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/27/2024] [Indexed: 10/05/2024]
Abstract
Sympathetic efferent renal nerves have key roles in the regulation of kidney function and blood pressure. Increased renal sympathetic nerve activity is thought to contribute to hypertension by promoting renal sodium retention, renin release and renal vasoconstriction. This hypothesis led to the development of catheter-based renal denervation (RDN) for the treatment of hypertension. Two RDN devices that ablate both efferent and afferent renal nerves received FDA approval for this indication in 2023. However, in animal models, selective ablation of afferent renal nerves resulted in comparable anti-hypertensive effects to ablation of efferent and afferent renal nerves and was associated with a reduction in sympathetic nerve activity. Selective afferent RDN also improved kidney function in a chronic kidney disease model. Notably, the beneficial effects of RDN extend beyond hypertension and chronic kidney disease to other clinical conditions that are associated with elevated sympathetic nerve activity, including heart failure and arrhythmia. These findings suggest that the kidney is an interoceptive organ, as increased renal sensory nerve activity modulates sympathetic activity to other organs. Future studies are needed to translate this knowledge into novel therapies for the treatment of hypertension and other cardiorenal diseases.
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Affiliation(s)
- Louise C Evans
- Department of Surgery, University of Minnesota, Minneapolis, MN, USA
| | - Alex Dayton
- Division of Nephrology and Hypertension, University of Minnesota, Minneapolis, MN, USA
| | - John W Osborn
- Department of Surgery, University of Minnesota, Minneapolis, MN, USA.
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4
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Evans LC, Dailey-Krempel B, Lauar MR, Dayton A, Vulchanova L, Osborn JW. Renal interoception in health and disease. Auton Neurosci 2024; 255:103208. [PMID: 39128142 DOI: 10.1016/j.autneu.2024.103208] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2024] [Revised: 07/19/2024] [Accepted: 07/26/2024] [Indexed: 08/13/2024]
Abstract
Catheter based renal denervation has recently been FDA approved for the treatment of hypertension. Traditionally, the anti-hypertensive effects of renal denervation have been attributed to the ablation of the efferent sympathetic renal nerves. In recent years the role of the afferent sensory renal nerves in the regulation of blood pressure has received increased attention. In addition, afferent renal denervation is associated with reductions in sympathetic nervous system activity. This suggests that reductions in sympathetic drive to organs other than the kidney may contribute to the non-renal beneficial effects observed in clinical trials of catheter based renal denervation. In this review we will provide an overview of the role of the afferent renal nerves in the regulation of renal function and the development of pathophysiologies, both renal and non-renal. We will also describe the central projections of the afferent renal nerves, to give context to the responses seen following their ablation and activation. Finally, we will discuss the emerging role of the kidney as an interoceptive organ. We will describe the potential role of the kidney in the regulation of interoceptive sensitivity and in this context, speculate on the possible pathological consequences of altered renal function.
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Affiliation(s)
- Louise C Evans
- Department of Surgery, University of Minnesota Medical School, Minneapolis 55455, United States of America
| | - Brianna Dailey-Krempel
- Department of Neuroscience, University of Minnesota, Minneapolis 55455, United States of America
| | - Mariana R Lauar
- Department of Surgery, University of Minnesota Medical School, Minneapolis 55455, United States of America
| | - Alex Dayton
- Division of Nephrology and Hypertension, University of Minnesota Medical School, Minneapolis 55455, United States of America
| | - Lucy Vulchanova
- Department of Neuroscience, University of Minnesota, Minneapolis 55455, United States of America
| | - John W Osborn
- Department of Surgery, University of Minnesota Medical School, Minneapolis 55455, United States of America.
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Brauer NR, Kempen AL, Hernandez D, Sintim HO. Non-kinase off-target inhibitory activities of clinically-relevant kinase inhibitors. Eur J Med Chem 2024; 275:116540. [PMID: 38852338 PMCID: PMC11243610 DOI: 10.1016/j.ejmech.2024.116540] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/27/2024] [Revised: 05/07/2024] [Accepted: 05/26/2024] [Indexed: 06/11/2024]
Abstract
Protein kinases are responsible for a myriad of cellular functions, such as cell cycle, apoptosis, and proliferation. Because of this, kinases make excellent targets for therapeutics. During the process to identify clinical kinase inhibitor candidates, kinase selectivity profiles of lead inhibitors are typically obtained. Such kinome selectivity screening could identify crucial kinase anti-targets that might contribute to drug toxicity and/or reveal additional kinase targets that potentially contribute to the efficacy of the compound via kinase polypharmacology. In addition to kinome panel screening, practitioners also obtain the inhibition profiles of a few non-kinase targets, such as ion-channels and select GPCR targets to identify compounds that might possess potential liabilities. Often ignored is the possibility that identified kinase inhibitors might also inhibit or bind to the other proteins (greater than 20,000) in the cell that are not kinases, which may be relevant to toxicity or even additional mode of drug action. This review highlights various inhibitors, which have been approved by the FDA or are currently undergoing clinical trials, that also inhibit other non-kinase targets. The binding poses of the drugs in the binding sites of the target kinases and off-targets are analyzed to understand if the same features of the compounds are critical for the polypharmacology.
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Affiliation(s)
- Nickolas R Brauer
- Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA
| | - Allison L Kempen
- Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA
| | - Delmis Hernandez
- Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA
| | - Herman O Sintim
- Department of Chemistry, Purdue University, 560 Oval Drive, West Lafayette, IN, 47907, USA; Purdue Institute for Drug Discovery, 720 Clinic Drive, West Lafayette, IN, 47907, USA; Purdue Institute for Cancer Research, 201 S. University St., West Lafayette, IN, 47907, USA.
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6
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Kotani Y, Belletti A, Maiucci G, Lodovici M, Fresilli S, Landoni G, Bellomo R, Zarbock A. Renin as a Prognostic Marker in Intensive Care and Perioperative Settings: A Scoping Review. Anesth Analg 2024; 138:929-936. [PMID: 38358109 DOI: 10.1213/ane.0000000000006682] [Citation(s) in RCA: 6] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/16/2024]
Abstract
Serum renin increases in response to sympathetic nerve activation and hypotension. Recent studies have reported the association of serum renin levels with adverse clinical outcomes in acute care settings. This scoping review aimed to systematically review the available literature on renin as a prognostic marker in intensive care and perioperative patients. We searched for studies published since inception until March 31, 2023, which assessed the association between serum renin levels and clinical outcomes or the effect of synthetic angiotensin II administration on serum renin levels in critically ill and perioperative patients in PubMed, Embase, and the Cochrane Library. The primary outcome was mortality at the longest follow-up; the secondary outcomes were adverse renal outcomes (ie, acute kidney injury, the need for renal replacement therapy, and major adverse kidney events), hemodynamic instability, outcomes to angiotensin II administration, and prognostic performance for mortality when compared with lactate. Among the 2081 studies identified, we included 16 studies with 1573 patients (7 studies on shock, 5 on nonspecific critical illness, 2 on cardiac surgery, 1 on noncardiac surgery, and 1 on coronavirus disease 2019). A significant association between serum renin levels and poor outcomes was identified in 14 studies, with 10 studies demonstrating an association with mortality. One post hoc analysis found that angiotensin II administration reduced mortality in patients with markedly elevated renin values. Two studies showed that renin was superior to lactate as a prognostic marker of mortality. Our scoping review showed that elevated serum renin levels may be associated with clinically relevant outcomes among various perioperative and intensive care populations. Increased serum renin levels may identify patients in which synthetic angiotensin II administration improves clinical outcomes and may outperform serum lactate in predicting mortality.
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Affiliation(s)
- Yuki Kotani
- From the Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
- Department of Intensive Care Medicine, Kameda Medical Center, Kamogawa, Japan
| | - Alessandro Belletti
- From the Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giacomo Maiucci
- From the Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Martina Lodovici
- From the Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Stefano Fresilli
- From the Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Giovanni Landoni
- From the Department of Anesthesia and Intensive Care, IRCCS San Raffaele Scientific Institute, Milan, Italy
- School of Medicine, Vita-Salute San Raffaele University, Milan, Italy
| | - Rinaldo Bellomo
- Department of Critical Care, The University of Melbourne, Melbourne, Victoria, Australia
- Department of Critical Care, Australian and New Zealand Intensive Care Research Centre, Monash University, Melbourne, Victoria, Australia
| | - Alexander Zarbock
- Department of Anesthesiology, Intensive Care Medicine and Pain Therapy, University Hospital Muenster, Muenster, Germany
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Maryam, Varghese TP, B T. Unraveling the complex pathophysiology of heart failure: insights into the role of renin-angiotensin-aldosterone system (RAAS) and sympathetic nervous system (SNS). Curr Probl Cardiol 2024; 49:102411. [PMID: 38246316 DOI: 10.1016/j.cpcardiol.2024.102411] [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: 01/15/2024] [Accepted: 01/18/2024] [Indexed: 01/23/2024]
Abstract
Heart failure (HF) is a widespread disease with significantly elevated mortality, morbidity, and hospitalization rates. Dysregulation of the sympathetic nervous system (SNS) and renin-angiotensin-aldosterone system (RAAS) are both postulated to be significant regulators of cardiovascular function, thereby playing a pivotal role in its pathophysiology. The RAAS is a sophisticated hormonal system that controls electrolyte homeostasis, fluid balance, and blood pressure. Angiotensin II, which operates to constrict blood vessels and raise blood pressure, is its principal effector molecule. The RAAS is frequently hyperactive in HF, which increases fluid retention and worsens cardiac function. The SNS is frequently hyperactive in heart failure, which increases the workload on the heart and worsens symptoms. This review will discuss what is currently known about the pathophysiology of heart failure, specifically in the context of RAAS and the SNS, in-depth to emphasize the knowledge gap that necessitates more research.
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Affiliation(s)
- Maryam
- Department of Pharmacy Practice, Deccan School of Pharmacy, Nampally, Hyderabad, Telangana, India; Department of Pharmacy Practice, Yenepoya Pharmacy College & Research centre, Yenepoya (Deemed to be University), Ayush campus, Naringana, Deralakatte, Mangalore, Karnataka, India
| | - Treesa P Varghese
- Department of Pharmacy Practice, Yenepoya Pharmacy College & Research centre, Yenepoya (Deemed to be University), Ayush campus, Naringana, Deralakatte, Mangalore, Karnataka, India.
| | - Tazneem B
- Department of Pharmacy Practice, Deccan School of Pharmacy, Nampally, Hyderabad, Telangana, India; Department of Pharmacy Practice, Yenepoya Pharmacy College & Research centre, Yenepoya (Deemed to be University), Ayush campus, Naringana, Deralakatte, Mangalore, Karnataka, India
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Hendry E, McCallister B, Elman DJ, Freeman R, Borsook D, Elman I. Validity of mental and physical stress models. Neurosci Biobehav Rev 2024; 158:105566. [PMID: 38307304 PMCID: PMC11082879 DOI: 10.1016/j.neubiorev.2024.105566] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2023] [Revised: 01/13/2024] [Accepted: 01/27/2024] [Indexed: 02/04/2024]
Abstract
Different stress models are employed to enhance our understanding of the underlying mechanisms and explore potential interventions. However, the utility of these models remains a critical concern, as their validities may be limited by the complexity of stress processes. Literature review revealed that both mental and physical stress models possess reasonable construct and criterion validities, respectively reflected in psychometrically assessed stress ratings and in activation of the sympathoadrenal system and the hypothalamic-pituitary-adrenal axis. The findings are less robust, though, in the pharmacological perturbations' domain, including such agents as adenosine or dobutamine. Likewise, stress models' convergent- and discriminant validity vary depending on the stressors' nature. Stress models share similarities, but also have important differences regarding their validities. Specific traits defined by the nature of the stressor stimulus should be taken into consideration when selecting stress models. Doing so can personalize prevention and treatment of stress-related antecedents, its acute processing, and chronic sequelae. Further work is warranted to refine stress models' validity and customize them so they commensurate diverse populations and circumstances.
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Affiliation(s)
- Erin Hendry
- Center for Autonomic and Peripheral Nerve Disorders, Harvard Medical School, Boston, MA, USA; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Brady McCallister
- Center for Autonomic and Peripheral Nerve Disorders, Harvard Medical School, Boston, MA, USA
| | - Dan J Elman
- Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Roy Freeman
- Center for Autonomic and Peripheral Nerve Disorders, Harvard Medical School, Boston, MA, USA; Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - David Borsook
- Departments of Psychiatry and Radiology, Massachusetts General Hospital, Harvard Medical School, Department of Anesthesiology, Harvard Medical School, Boston, MA, USA.
| | - Igor Elman
- Department of Psychiatry, Cambridge Health Alliance, Harvard Medical School, Cambridge, MA, USA
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Coste B, Delmas P. PIEZO Ion Channels in Cardiovascular Functions and Diseases. Circ Res 2024; 134:572-591. [PMID: 38422173 DOI: 10.1161/circresaha.123.322798] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 03/02/2024]
Abstract
The cardiovascular system provides blood supply throughout the body and as such is perpetually applying mechanical forces to cells and tissues. Thus, this system is primed with mechanosensory structures that respond and adapt to changes in mechanical stimuli. Since their discovery in 2010, PIEZO ion channels have dominated the field of mechanobiology. These have been proposed as the long-sought-after mechanosensitive excitatory channels involved in touch and proprioception in mammals. However, more and more pieces of evidence point to the importance of PIEZO channels in cardiovascular activities and disease development. PIEZO channel-related cardiac functions include transducing hemodynamic forces in endothelial and vascular cells, red blood cell homeostasis, platelet aggregation, and arterial blood pressure regulation, among others. PIEZO channels contribute to pathological conditions including cardiac hypertrophy and pulmonary hypertension and congenital syndromes such as generalized lymphatic dysplasia and xerocytosis. In this review, we highlight recent advances in understanding the role of PIEZO channels in cardiovascular functions and diseases. Achievements in this quickly expanding field should open a new road for efficient control of PIEZO-related diseases in cardiovascular functions.
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Affiliation(s)
- Bertrand Coste
- Centre de Recherche en CardioVasculaire et Nutrition, Aix-Marseille Université - INSERM 1263 - INRAE 1260, Marseille, France
| | - Patrick Delmas
- Centre de Recherche en CardioVasculaire et Nutrition, Aix-Marseille Université - INSERM 1263 - INRAE 1260, Marseille, France
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Gawrys O, Husková Z, Škaroupková P, Honetschlägerová Z, Vaňourková Z, Kikerlová S, Melenovský V, Bačová BS, Sykora M, Táborský M, Červenka L. The treatment with sGC stimulator improves survival of hypertensive rats in response to volume-overload induced by aorto-caval fistula. NAUNYN-SCHMIEDEBERG'S ARCHIVES OF PHARMACOLOGY 2023; 396:3757-3773. [PMID: 37338578 PMCID: PMC10643302 DOI: 10.1007/s00210-023-02561-y] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/28/2023] [Accepted: 05/30/2023] [Indexed: 06/21/2023]
Abstract
Heart failure (HF) has been declared as global pandemic and current therapies are still ineffective, especially in patients that develop concurrent cardio-renal syndrome. Considerable attention has been focused on the nitric oxide (NO)/soluble guanylyl cyclase (sGC)/cyclic guanosine monophosphate (cGMP) pathway. In the current study, we aimed to investigate the effectiveness of sGC stimulator (BAY41-8543) with the same mode of action as vericiguat, for the treatment of heart failure (HF) with cardio-renal syndrome. As a model, we chose heterozygous Ren-2 transgenic rats (TGR), with high-output heart failure, induced by aorto-caval fistula (ACF). The rats were subjected into three experimental protocols to evaluate short-term effects of the treatment, impact on blood pressure, and finally the long-term survival lasting 210 days. As control groups, we used hypertensive sham TGR and normotensive sham HanSD rats. We have shown that the sGC stimulator effectively increased the survival of rats with HF in comparison to untreated animals. After 60 days of sGC stimulator treatment, the survival was still 50% compared to 8% in the untreated rats. One-week treatment with sGC stimulator increased the excretion of cGMP in ACF TGR (109 ± 28 nnmol/12 h), but the ACE inhibitor decreased it (-63 ± 21 nnmol/12 h). Moreover, sGC stimulator caused a decrease in SBP, but this effect was only temporary (day 0: 117 ± 3; day 2: 108 ± 1; day 14: 124 ± 2 mmHg). These results support the concept that sGC stimulators might represent a valuable class of drugs to battle heart failure especially with cardio-renal syndrome, but further studies are necessary.
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Affiliation(s)
- Olga Gawrys
- Experimental Medicine Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic.
| | - Zuzana Husková
- Experimental Medicine Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Petra Škaroupková
- Experimental Medicine Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Zuzana Honetschlägerová
- Experimental Medicine Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Zdeňka Vaňourková
- Experimental Medicine Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Soňa Kikerlová
- Experimental Medicine Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Vojtěch Melenovský
- Department of Cardiology, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
| | - Barbara Szeiffová Bačová
- Centre of Experimental Medicine, Slovak Academy of Sciences, Institute for Heart Research, Bratislava, Slovakia
| | - Matúš Sykora
- Centre of Experimental Medicine, Slovak Academy of Sciences, Institute for Heart Research, Bratislava, Slovakia
| | - Miloš Táborský
- Department of Internal Medicine I, Cardiology, University Hospital Olomouc and Palacký University, Olomouc, Czech Republic
| | - Luděk Červenka
- Experimental Medicine Centre, Institute for Clinical and Experimental Medicine, Prague, Czech Republic
- Department of Internal Medicine I, Cardiology, University Hospital Olomouc and Palacký University, Olomouc, Czech Republic
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Chiu CH, Hsuan CF, Lin SH, Hung YJ, Hwu CM, Hee SW, Lin SW, Fong SW, Hsieh PCH, Yang WS, Lin WC, Lee HL, Hsieh ML, Li WY, Lin JW, Hsu CN, Wu VC, Chuang GT, Chang YC, Chuang LM. ER ribosomal-binding protein 1 regulates blood pressure and potassium homeostasis by modulating intracellular renin trafficking. J Biomed Sci 2023; 30:13. [PMID: 36803854 PMCID: PMC9940419 DOI: 10.1186/s12929-023-00905-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2022] [Accepted: 02/07/2023] [Indexed: 02/21/2023] Open
Abstract
BACKGROUND Genome-wide association studies (GWASs) have linked RRBP1 (ribosomal-binding protein 1) genetic variants to atherosclerotic cardiovascular diseases and serum lipoprotein levels. However, how RRBP1 regulates blood pressure is unknown. METHODS To identify genetic variants associated with blood pressure, we performed a genome-wide linkage analysis with regional fine mapping in the Stanford Asia-Pacific Program for Hypertension and Insulin Resistance (SAPPHIRe) cohort. We further investigated the role of the RRBP1 gene using a transgenic mouse model and a human cell model. RESULTS In the SAPPHIRe cohort, we discovered that genetic variants of the RRBP1 gene were associated with blood pressure variation, which was confirmed by other GWASs for blood pressure. Rrbp1- knockout (KO) mice had lower blood pressure and were more likely to die suddenly from severe hyperkalemia caused by phenotypically hyporeninemic hypoaldosteronism than wild-type controls. The survival of Rrbp1-KO mice significantly decreased under high potassium intake due to lethal hyperkalemia-induced arrhythmia and persistent hypoaldosteronism, which could be rescued by fludrocortisone. An immunohistochemical study revealed renin accumulation in the juxtaglomerular cells of Rrbp1-KO mice. In the RRBP1-knockdown Calu-6 cells, a human renin-producing cell line, transmission electron and confocal microscopy revealed that renin was primarily retained in the endoplasmic reticulum and was unable to efficiently target the Golgi apparatus for secretion. CONCLUSIONS RRBP1 deficiency in mice caused hyporeninemic hypoaldosteronism, resulting in lower blood pressure, severe hyperkalemia, and sudden cardiac death. In juxtaglomerular cells, deficiency of RRBP1 reduced renin intracellular trafficking from ER to Golgi apparatus. RRBP1 is a brand-new regulator of blood pressure and potassium homeostasis discovered in this study.
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Affiliation(s)
- Chu-Hsuan Chiu
- Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, 100, Taiwan
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan
| | - Chin-Feng Hsuan
- Division of Cardiology, Department of Internal Medicine, E-Da Hospital, Kaohsiung, 824410, Taiwan
- Division of Cardiology, Department of Internal Medicine, E-Da Dachang Hospital, Kaohsiung, 82445, Taiwan
- School of Medicine, College of Medicine, I-Shou University, Kaohsiung, 840203, Taiwan
| | - Shih-Hua Lin
- Graduate Institute of Medical Science, National Defense Medical Center, Taipei, 114, Taiwan
- Section of General Medicine, Department of Medicine, Taipei Veterans General Hospital, Taipei, 111, Taiwan
| | - Yi-Jen Hung
- Division of Endocrinology and Metabolism, Department of Internal Medicine, Tri-Service General Hospital, National Defense Medical Center, Taipei, 100, Taiwan
| | - Chii-Min Hwu
- Faculty of Medicine, National Yang-Ming University School of Medicine, Taipei, 112, Taiwan
- Division of Nephrology, Department of Medicine, Tri-Service General Hospital, Taipei, 114, Taiwan
| | - Siow-Wey Hee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan
| | - Shu-Wha Lin
- Division of Genomic Medicine, Research Center for Medical Excellence, Transgenic Mouse Models Core, National Taiwan University, Taipei, 100, Taiwan
| | - Sitt-Wai Fong
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan
| | | | - Wei-Shun Yang
- Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, 100, Taiwan
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Hsin-Chu Branch, Hsin-Chu, 302, Taiwan
| | - Wei-Chou Lin
- Department of Pathology, National Taiwan University Hospital, Taipei, 100, Taiwan
| | - Hsiao-Lin Lee
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan
| | - Meng-Lun Hsieh
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan
- Department of Medicinal Chemistry, College of Pharmacy, University of Florida, Gainesville, FL, 32610, USA
| | - Wen-Yi Li
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin, 640, Taiwan
| | - Jou-Wei Lin
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin, 640, Taiwan
| | - Chih-Neng Hsu
- Division of Cardiology, Department of Internal Medicine, National Taiwan University Hospital Yunlin Branch, Yunlin, 640, Taiwan
| | - Vin-Cent Wu
- Division of Nephrology, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan
| | - Gwo-Tsann Chuang
- Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, 100, Taiwan
- Department of Pediatrics, National Taiwan University Hospital, College of Medicine, National Taiwan University, Taipei, 100, Taiwan
| | - Yi-Cheng Chang
- Graduate Institute of Medical Genomics and Proteomics, National Taiwan University, Taipei, 100, Taiwan.
- Institute of Biomedical Sciences, Academia Sinica, Taipei, 115, Taiwan.
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan.
- Graduate Institute of Molecular Medicine, National Taiwan University, Taipei, 100, Taiwan.
| | - Lee-Ming Chuang
- Division of Endocrinology and Metabolism, Department of Internal Medicine, National Taiwan University Hospital, Taipei, 100, Taiwan.
- Graduate Institute of Molecular Medicine, National Taiwan University, Taipei, 100, Taiwan.
- Graduate Institute of Clinical Medicine, National Taiwan University, Taipei, 100, Taiwan.
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12
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Saito N, Toyoda M, Kondo M, Abe M, Sanechika N, Kimura M, Sawada K, Fukagawa M. Regulation of Renin Expression by Β1-Integrin in As4.1 Juxtaglomerular Line Cells. Biomedicines 2023; 11:biomedicines11020501. [PMID: 36831037 PMCID: PMC9953579 DOI: 10.3390/biomedicines11020501] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 02/06/2023] [Accepted: 02/08/2023] [Indexed: 02/12/2023] Open
Abstract
(1) Background: Renal dysfunction and hypertension are mutually aggravating factors; however, the details of their interaction remain unclear. In a study using renal tissue from diabetic rats, we found that β1-integrin, a cell-substrate adhesion molecule, is specifically phosphorylated in juxtaglomerular cells that secrete renin, a blood pressure regulator. (2) Methods: A mouse juxtaglomerular cell line (As4.1 cells) was used for the following experiments: drug-induced promotion of β1-integrin phosphorylation/dephosphorylation; knockdown of β1-integrin and the cell adhesion molecule connexin-40 (a candidate for the main body of baroreceptor); and pressurization to atmospheric pressure + 100 mmHg. culture in hypotonic liquid medium. The expression of renin under these conditions was measured by qRT-PCR. (3) Results: Phosphorylation of β1-integrin suppressed the expression of renin, while dephosphorylation conversely promoted it. β1-integrin and connexin-40 knockdown both promoted the expression of renin. Pneumatic pressurization and hypotonic medium culture both decreased the expression of renin, which was restored by the knockdown of β1-integrin. (4) Conclusions: β1-integrin plays an inhibitory role in the regulation of the expression of renin, which may be controlled by phosphorylation and dephosphorylation. It is hypothesized that β1-integrin and other adhesion factors regulate the expression of renin by altering the sensitivity of baroreceptors on the plasma membrane.
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Affiliation(s)
| | - Masao Toyoda
- Correspondence: ; Tel.: +81-463-93-1121 (ext. 2490)
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13
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Sharma H, Raju B, Narendra G, Motiwale M, Sharma B, Verma H, Silakari O. QM/MM Studies on Enzyme Catalysis and Insight into Designing of New Inhibitors by ONIOM Approach: Recent Update. ChemistrySelect 2023. [DOI: 10.1002/slct.202203319] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023]
Affiliation(s)
- Himani Sharma
- Molecular Modeling Lab (MML) Department of Pharmaceutical Sciences and Drug Research Punjabi University Patiala Punjab 147002 India
| | - Baddipadige Raju
- Molecular Modeling Lab (MML) Department of Pharmaceutical Sciences and Drug Research Punjabi University Patiala Punjab 147002 India
| | - Gera Narendra
- Molecular Modeling Lab (MML) Department of Pharmaceutical Sciences and Drug Research Punjabi University Patiala Punjab 147002 India
| | - Mohit Motiwale
- Molecular Modeling Lab (MML) Department of Pharmaceutical Sciences and Drug Research Punjabi University Patiala Punjab 147002 India
| | - Bhavna Sharma
- Molecular Modeling Lab (MML) Department of Pharmaceutical Sciences and Drug Research Punjabi University Patiala Punjab 147002 India
| | - Himanshu Verma
- Molecular Modeling Lab (MML) Department of Pharmaceutical Sciences and Drug Research Punjabi University Patiala Punjab 147002 India
| | - Om Silakari
- Molecular Modeling Lab (MML) Department of Pharmaceutical Sciences and Drug Research Punjabi University Patiala Punjab 147002 India
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14
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Issotina Zibrila A, Wang Z, Sangaré-Oumar MM, Zeng M, Liu X, Wang X, Zeng Z, Kang YM, Liu J. Role of blood-borne factors in sympathoexcitation-mediated hypertension: Potential neurally mediated hypertension in preeclampsia. Life Sci 2022; 320:121351. [PMID: 36592790 DOI: 10.1016/j.lfs.2022.121351] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Revised: 12/19/2022] [Accepted: 12/27/2022] [Indexed: 01/01/2023]
Abstract
Hypertension remains a threat for society due to its unknown causes, preventing proper management, for the growing number of patients, for its state as a high-risk factor for stroke, cardiac and renal complication and as cause of disability. Data from clinical and animal researches have suggested the important role of many soluble factors in the pathophysiology of hypertension through their neuro-stimulating effects. Central targets of these factors are of molecular, cellular and structural nature. Preeclampsia (PE) is characterized by high level of soluble factors with strong pro-hypertensive activity and includes immune factors such as proinflammatory cytokines (PICs). The potential neural effect of those factors in PE is still poorly understood. Shedding light into the potential central effect of the soluble factors in PE may advance our current comprehension of the pathophysiology of hypertension in PE, which will contribute to better management of the disease. In this paper, we summarized existing data in respect of hypothesis of this review, that is, the existence of the neural component in the pathophysiology of the hypertension in PE. Future studies would address this hypothesis to broaden our understanding of the pathophysiology of hypertension in PE.
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Affiliation(s)
- Abdoulaye Issotina Zibrila
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases, Xi'an 710061, Shaanxi, PR China; Department of Animal Physiology, Faculty of science and Technology, University of Abomey-Calavi, 06 BP 2584 Cotonou, Benin
| | - Zheng Wang
- Key Laboratory of Shaanxi Province for Craniofacial Precision Medicine Research, College of Stomatology, Xi'an Jiaotong University, PR China
| | - Machioud Maxime Sangaré-Oumar
- Department of Animal Physiology, Faculty of science and Technology, University of Abomey-Calavi, 06 BP 2584 Cotonou, Benin
| | - Ming Zeng
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases, Xi'an 710061, Shaanxi, PR China
| | - Xiaoxu Liu
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases, Xi'an 710061, Shaanxi, PR China
| | - Xiaomin Wang
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases, Xi'an 710061, Shaanxi, PR China
| | - Zhaoshu Zeng
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases, Xi'an 710061, Shaanxi, PR China
| | - Yu-Ming Kang
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases, Xi'an 710061, Shaanxi, PR China.
| | - Jinjun Liu
- Department of Physiology and Pathophysiology, Xi'an Jiaotong University School of Basic Medical Sciences, Key Laboratory of Environment and Genes Related to Diseases, Xi'an 710061, Shaanxi, PR China.
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15
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Fargieva KR, Guseinova RM, Pigarova EA, Dzeranova LK. The role of the apelin/APJ system in water homeostasis regulation. OBESITY AND METABOLISM 2022. [DOI: 10.14341/omet12752] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Water balance in the body is achieved by balancing renal and non-renal water losses with corresponding water intake. It is under the control of both the central nervous system, which integrates many parameters of water and electrolyte balance in the body, including inducing important adaptive behavioral responses, and three hormonal systems: vasopressinergic, renin-angiotensin-aldosterone and apelinergic. A lot of research is devoted to the regulation of water-electrolyte metabolism. However, this process is still quite difficult to understand, especially since more and more of its regulators are being discovered over time. One of them is the hormone apelin, an endogenous ligand for the APJ receptor. As is known, the receptor is highly expressed in many organs, such as the brain, heart, liver and kidneys, lungs, and has multidirectional effects.This literature review discusses the main characteristics and features of the regulation of these systems in relation to water-electrolyte metabolism, as well as issues of intersystem interaction and modulation of the effects of apelin.
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16
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Yang X, Zeng H, Wang L, Luo S, Zhou Y. Activation of Piezo1 downregulates renin in juxtaglomerular cells and contributes to blood pressure homeostasis. Cell Biosci 2022; 12:197. [PMID: 36471394 PMCID: PMC9720979 DOI: 10.1186/s13578-022-00931-2] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Accepted: 11/17/2022] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The synthesis and secretion of renin in juxtaglomerular (JG) cells are closely regulated by the blood pressure. To date, however, the molecular identity through which JG cells respond to the blood pressure remains unclear. RESULTS Here we discovered that Piezo1, a mechanosensitive ion channel, was colocalized with renin in mouse kidney as well as As4.1 cells, a commonly used JG cell line. Activation of Piezo1 by its agonist Yoda1 induced an intracellular calcium increase and downregulated the expression of renin in these cells, while knockout of Piezo1 in JG cells abolished the effect of Yoda1. Meanwhile, mechanical stress using microfluidics also induced an intracellular calcium increase in wildtype but not Piezo1 knockout JG cells. Mechanistically, we demonstrated that activation of Piezo1 upregulated the Ptgs2 expression via the calcineurin-NFAT pathway and increased the production of Ptgs2 downstream molecule PGE2 in JG cells. Surprisingly, we discovered that increased PGE2 could decreased the renin expression through the PGE2 receptor EP1 and EP3, which inhibited the cAMP production in JG cells. In mice, we found that activation of Piezo1 significantly downregulated the renin expression and blood pressure in wildtype but not adeno-associated virus (AAV)-mediated kidney specific Piezo1 knockdown mice. CONCLUSIONS In summary, these results revealed that activation of Piezo1 could downregulate the renin expression in JG cells and mice, subsequently a reduction of blood pressure, highlighting its therapeutic potential as a drug target of the renin-angiotensin system.
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Affiliation(s)
- Xiaoqiang Yang
- grid.412536.70000 0004 1791 7851Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 China ,grid.412536.70000 0004 1791 7851Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 Guangdong China
| | - Honghui Zeng
- grid.412536.70000 0004 1791 7851Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 China ,grid.412536.70000 0004 1791 7851Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 Guangdong China
| | - Le Wang
- grid.412536.70000 0004 1791 7851Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 China ,grid.412536.70000 0004 1791 7851Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 Guangdong China
| | - Siweier Luo
- grid.412536.70000 0004 1791 7851Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 China ,grid.412536.70000 0004 1791 7851Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 Guangdong China
| | - Yiming Zhou
- grid.412536.70000 0004 1791 7851Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Guangdong-Hong Kong Joint Laboratory for RNA Medicine, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 China ,grid.412536.70000 0004 1791 7851Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou, 510120 Guangdong China
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17
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do Nascimento NC, Bailey TW, Santos AP, Duan C, Mohallem R, Franco J, Aryal UK, Xie J, Cox A, Sivasankar MP. Proteomic analysis reveals that aging rabbit vocal folds are more vulnerable to changes caused by systemic dehydration. BMC Genomics 2022; 23:762. [PMID: 36411412 PMCID: PMC9677652 DOI: 10.1186/s12864-022-08975-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2022] [Accepted: 10/27/2022] [Indexed: 11/22/2022] Open
Abstract
BACKGROUND Older adults are more prone to develop systemic dehydration. Systemic dehydration has implications for vocal fold biology by affecting gene and protein expression. The objective of this study was to quantify vocal fold protein changes between two age groups and hydration status, and to investigate the interaction of age and hydration status on protein expression, which has not been investigated in the context of vocal folds before. Comparative proteomics was used to analyze the vocal fold proteome of 6.5-month-old and > 3-year-old rabbits subjected to water ad libitum or water volume restriction protocol. RESULTS Young and older adult rabbits (n = 22) were either euhydrated (water ad libitum) or dehydrated by water volume restriction. Dehydration was confirmed by body weight loss of - 5.4% and - 4.6% in young and older groups, respectively, and a 1.7-fold increase of kidney renin gene expression in the young rabbits. LC-MS/MS identified 2286 proteins in the rabbit vocal folds of young and older adult rabbits combined. Of these, 177, 169, and 81 proteins were significantly (p ≤ 0.05) affected by age, hydration status, or the interaction of both factors, respectively. Analysis of the interaction effect revealed 32 proteins with opposite change patterns after dehydration between older and young rabbit vocal folds, while 31 proteins were differentially regulated only in the older adult rabbits and ten only in the young rabbits in response to systemic dehydration. The magnitude of changes for either up or downregulated proteins was higher in the older rabbits. These proteins are predominantly related to structural components of the extracellular matrix and muscle layer, suggesting a disturbance in the viscoelastic properties of aging vocal fold tissue, especially when subjected to systemic dehydration. CONCLUSIONS Water restriction is a laboratory protocol to assess systemic dehydration-related changes in the vocal fold tissue that is translatable to human subjects. Our findings showed a higher number of proteins differentially regulated with a greater magnitude of change in the vocal folds of older adult rabbits in the presence of systemic dehydration compared to younger rabbits. The association of these proteins with vocal fold structure and biomechanical properties suggests that older human subjects may be more vulnerable to the effects of systemic dehydration on vocal function. The clinical implications of these protein changes warrant more investigation, but age should be taken into consideration when evaluating vocal treatment recommendations that interfere with body fluid balance.
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Affiliation(s)
- Naila C. do Nascimento
- grid.169077.e0000 0004 1937 2197Department of Speech, Language, and Hearing Sciences, Purdue University, West Lafayette, Indiana, 47907 USA
| | - Taylor W. Bailey
- grid.169077.e0000 0004 1937 2197Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana, 47907 USA
| | - Andrea P. Santos
- grid.169077.e0000 0004 1937 2197Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana, 47907 USA
| | - Chenwei Duan
- grid.169077.e0000 0004 1937 2197Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, 47907 USA
| | - Rodrigo Mohallem
- grid.169077.e0000 0004 1937 2197Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana, 47907 USA ,grid.169077.e0000 0004 1937 2197Purdue Proteomics Facility, Bindley Bioscience Center, Discovery Park, Purdue University, West Lafayette, Indiana, 47907 USA
| | - Jackeline Franco
- grid.169077.e0000 0004 1937 2197Purdue Proteomics Facility, Bindley Bioscience Center, Discovery Park, Purdue University, West Lafayette, Indiana, 47907 USA
| | - Uma K. Aryal
- grid.169077.e0000 0004 1937 2197Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana, 47907 USA ,grid.169077.e0000 0004 1937 2197Purdue Proteomics Facility, Bindley Bioscience Center, Discovery Park, Purdue University, West Lafayette, Indiana, 47907 USA
| | - Jun Xie
- grid.169077.e0000 0004 1937 2197Department of Statistics, Purdue University, West Lafayette, Indiana, 47907 USA
| | - Abigail Cox
- grid.169077.e0000 0004 1937 2197Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana, 47907 USA
| | - M. Preeti Sivasankar
- grid.169077.e0000 0004 1937 2197Department of Speech, Language, and Hearing Sciences, Purdue University, West Lafayette, Indiana, 47907 USA
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18
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Rafaqat S, Afzal S, Rafaqat S, Khurshid H, Rafaqat S. Cardiac markers: Role in the pathogenesis of arterial hypertension. World J Hypertens 2022; 10:1-14. [DOI: 10.5494/wjh.v10.i1.1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2022] [Revised: 09/03/2022] [Accepted: 10/14/2022] [Indexed: 02/08/2023] Open
Affiliation(s)
- Saira Rafaqat
- Department of Zoology, Lahore College for Women University, Lahore 5400, Pakistan
| | - Shaheed Afzal
- Emergency Department of Cardiology, Punjab Institute of Cardiology, Lahore 5400, Pakistan
| | - Sana Rafaqat
- Department of Biotechnology, Lahore College for Women University, Lahore 5400, Pakistan
| | - Huma Khurshid
- Department of Zoology, Lahore College for Women University, Lahore 5400, Pakistan
| | - Simon Rafaqat
- Department of Business, Forman Christian College, Lahore 5400, Pakistan
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19
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Skolnick J, Zhou H. Implications of the Essential Role of Small Molecule Ligand Binding Pockets in Protein-Protein Interactions. J Phys Chem B 2022; 126:6853-6867. [PMID: 36044742 PMCID: PMC9484464 DOI: 10.1021/acs.jpcb.2c04525] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Revised: 08/18/2022] [Indexed: 11/28/2022]
Abstract
Protein-protein interactions (PPIs) and protein-metabolite interactions play a key role in many biochemical processes, yet they are often viewed as being independent. However, the fact that small molecule drugs have been successful in inhibiting PPIs suggests a deeper relationship between protein pockets that bind small molecules and PPIs. We demonstrate that 2/3 of PPI interfaces, including antibody-epitope interfaces, contain at least one significant small molecule ligand binding pocket. In a representative library of 50 distinct protein-protein interactions involving hundreds of mutations, >75% of hot spot residues overlap with small molecule ligand binding pockets. Hence, ligand binding pockets play an essential role in PPIs. In representative cases, evolutionary unrelated monomers that are involved in different multimeric interactions yet share the same pocket are predicted to bind the same metabolites/drugs; these results are confirmed by examples in the PDB. Thus, the binding of a metabolite can shift the equilibrium between monomers and multimers. This implicit coupling of PPI equilibria, termed "metabolic entanglement", was successfully employed to suggest novel functional relationships among protein multimers that do not directly interact. Thus, the current work provides an approach to unify metabolomics and protein interactomics.
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Affiliation(s)
- Jeffrey Skolnick
- Center for the Study of Systems
Biology, School of Biological Sciences, Georgia Institute of Technology, 950 Atlantic Drive, NW, Atlanta, Georgia 30332, United States
| | - Hongyi Zhou
- Center for the Study of Systems
Biology, School of Biological Sciences, Georgia Institute of Technology, 950 Atlantic Drive, NW, Atlanta, Georgia 30332, United States
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20
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Interactions between the intrarenal dopaminergic and the renin-angiotensin systems in the control of systemic arterial pressure. Clin Sci (Lond) 2022; 136:1205-1227. [PMID: 35979889 DOI: 10.1042/cs20220338] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Revised: 07/31/2022] [Accepted: 08/03/2022] [Indexed: 11/17/2022]
Abstract
Systemic arterial hypertension is one of the leading causes of morbidity and mortality in the general population, being a risk factor for many cardiovascular diseases. Although its pathogenesis is complex and still poorly understood, some systems appear to play major roles in its development. This review aims to update the current knowledge on the interaction of the intrarenal renin-angiotensin system (RAS) and dopaminergic system in the development of hypertension, focusing on recent scientific hallmarks in the field. The intrarenal RAS, composed of several peptides and receptors, has a critical role in the regulation of blood pressure (BP) and, consequently, the development of hypertension. The RAS is divided into two main intercommunicating axes: the classical axis, composed of angiotensin-converting enzyme, angiotensin II, and angiotensin type 1 receptor, and the ACE2/angiotensin-(1-7)/Mas axis, which appears to modulate the effects of the classical axis. Dopamine and its receptors are also increasingly showing an important role in the pathogenesis of hypertension, as abnormalities in the intrarenal dopaminergic system impair the regulation of renal sodium transport, regardless of the affected dopamine receptor subtype. There are five dopamine receptors, which are divided into two major subtypes: the D1-like (D1R and D5R) and D2-like (D2R, D3R, and D4R) receptors. Mice deficient in any of the five dopamine receptor subtypes have increased BP. Intrarenal RAS and the dopaminergic system have complex interactions. The balance between both systems is essential to regulate the BP homeostasis, as alterations in the control of both can lead to hypertension.
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21
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Lara LS, Gonzalez AA, Hennrikus MT, Prieto MC. Hormone-Dependent Regulation of Renin and Effects on Prorenin Receptor Signaling in the Collecting Duct. Curr Hypertens Rev 2022; 18:91-100. [PMID: 35170417 PMCID: PMC10132771 DOI: 10.2174/1573402118666220216105357] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2021] [Revised: 10/22/2021] [Accepted: 12/13/2021] [Indexed: 01/27/2023]
Abstract
The production of renin by the principal cells of the collecting duct has widened our understanding of the regulation of intrarenal angiotensin II (Ang II) generation and blood pressure. In the collecting duct, Ang II increases the synthesis and secretion of renin by mechanisms involving the activation of Ang II type 1 receptor (AT1R) via stimulation of the PKCα, Ca2+, and cAMP/PKA/CREB pathways. Additionally, paracrine mediators, including vasopressin (AVP), prostaglandins, bradykinin (BK), and atrial natriuretic peptide (ANP), regulate renin in principal cells. During Ang II-dependent hypertension, despite plasma renin activity suppression, renin and prorenin receptor (RPR) are upregulated in the collecting duct and promote de novo formation of intratubular Ang II. Furthermore, activation of PRR by its natural agonists, prorenin and renin, may contribute to the stimulation of profibrotic factors independent of Ang II. Thus, the interactions of RAS components with paracrine hormones within the collecting duct enable tubular compartmentalization of the RAS to orchestrate complex mechanisms that increase intrarenal Ang II, Na+ reabsorption, and blood pressure.
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Affiliation(s)
- Lucienne S Lara
- Instituto de Ciencias Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Alexis A Gonzalez
- Instituto de Química, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Matthew T Hennrikus
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, USA
| | - Minolfa C Prieto
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, USA.,Tulane Renal and Hypertension Center of Excellence, Tulane University School of Medicine, New Orleans, LA, USA
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22
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Mukherjee T, Behl T, Sharma S, Sehgal A, Singh S, Sharma N, Mathew B, Kaur J, Kaur R, Das M, Aleya L, Bungau S. Anticipated pharmacological role of Aviptadil on COVID-19. ENVIRONMENTAL SCIENCE AND POLLUTION RESEARCH INTERNATIONAL 2022; 29:8109-8125. [PMID: 34846667 PMCID: PMC8630992 DOI: 10.1007/s11356-021-17824-5] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 11/24/2021] [Indexed: 04/16/2023]
Abstract
Vasoactive intestinal peptide (VIP) is a neuropeptide that is produced by the lymphoid cells and plays a major role in immunological functions for controlling the homeostasis of the immune system. VIP has been identified as a potent anti-inflammatory factor, in boosting both innate and adaptive immunity. Since December 2019, SARS-Cov-2 was found responsible for the disease COVID-19 which has spread worldwide. No specific therapies or 100% effective vaccines are yet available for the treatment of COVID-19. Drug repositioning may offer a strategy and several drugs have been repurposed, including lopinavir/ritonavir, remdesivir, favipiravir, and tocilizumab. This paper describes the main pharmacological properties of synthetic VIP drug (Aviptadil) which is now under clinical trials. A patented formulation of vasoactive intestinal polypeptide (VIP), named RLF-100 (Aviptadil), was developed and finally got approved for human trials by FDA in 2001 and in European medicines agency in 2005. It was awarded Orphan Drug Designation in 2001 by the US FDA for the treatment of acute respiratory distress syndrome and for the treatment of pulmonary arterial hypertension in 2005. Investigational new drug (IND) licenses for human trials of Aviptadil was guaranteed by both the US FDA and EMEA. Preliminary clinical trials seem to support Aviptadil's benefit. However, such drugs like Aviptadil in COVID-19 patients have peculiar safety profiles. Thus, adequate clinical trials are necessary for these compounds.
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Affiliation(s)
- Tuhin Mukherjee
- Guru Nanak Institute of Pharmaceutical Science and Technology, Kolkata, West Bengal, India
| | - Tapan Behl
- Chitkara College of Pharmacy, Chitkara University, Punjab, India.
| | - Sanchay Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Aayush Sehgal
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Sukhbir Singh
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Neelam Sharma
- Chitkara College of Pharmacy, Chitkara University, Punjab, India
| | - Bijo Mathew
- Department of Pharmaceutical Chemistry, Amrita School of Pharmacy, Amrita Vishwa Vidyapeetham, AIMS Health Science Campus, Kochi, India
| | - Jasleen Kaur
- Guru Nanak Institute of Pharmaceutical Science and Technology, Kolkata, West Bengal, India
| | - Ratandeep Kaur
- Guru Nanak Institute of Pharmaceutical Science and Technology, Kolkata, West Bengal, India
| | - Mayukh Das
- Guru Nanak Institute of Pharmaceutical Science and Technology, Kolkata, West Bengal, India
| | - Lotfi Aleya
- Chrono-Environment Laboratory, UMR CNRS 6249, Bourgogne Franche-Comté University, Besançon, France
| | - Simona Bungau
- Department of Pharmacy, Faculty of Medicine and Pharmacy, University of Oradea, Oradea, Romania
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Maideen NMP, Balasubramanian R, Muthusamy S, Nallasamy V. An Overview of Clinically Imperative and Pharmacodynamically Significant Drug Interactions of Renin-Angiotensin-Aldosterone System (RAAS) Blockers. Curr Cardiol Rev 2022; 18:e110522204611. [PMID: 35546745 PMCID: PMC9893153 DOI: 10.2174/1573403x18666220511152330] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/25/2022] [Revised: 02/26/2022] [Accepted: 03/28/2022] [Indexed: 11/22/2022] Open
Abstract
INTRODUCTION Hypertension is a leading cause of cardiovascular disease and chronic kidney disease, resulting in premature death and disability. The Renin-Angiotensin-Aldosterone System (RAAS) blockers, including Angiotensin-Converting Enzyme (ACE) inhibitors or Angiotensin Receptor Blockers (ARBs), are used as first-line antihypertensive therapy to treat hypertensive patients with comorbidities, including diabetes, ischemic heart disease, heart failure, and chronic kidney disease. The use of RAS blockers is associated with the risks, such as hyperkalemia, angioedema, etc. The drugs potentiating them interact pharmacodynamically, resulting in adverse consequences. This review article focuses on the clinically important drug interactions of RAAS blockers. MATERIALS AND METHODS The electronic databases, such as Medline/PubMed Central/PubMed, Google Scholar, ScienceDirect, Cochrane Library, Directory of Open Access Journals (DOAJ), Embase, and reference lists were searched to identify relevant articles. RESULTS The risk of hyperkalemia may be enhanced potentially in patients receiving a RAS blocker and potassium-sparing diuretics, potassium supplements, trimethoprim, adrenergic betablockers, antifungal agents, calcineurin inhibitors, pentamidine, heparins or an NSAID, concomitantly. The patients taking ACE inhibitors and mTOR inhibitors, DPP4 inhibitors, alteplase, or sacubitril/valsartan concurrently may be at increased risk of developing angioedema. CONCLUSION Clinicians, pharmacists, and other healthcare practitioners should be accountable for medication safety. To avoid adverse implications, prescribers and pharmacists must be aware of the drugs that interact with RAAS blockers.
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Affiliation(s)
| | | | - Sudha Muthusamy
- Department of Pharmacology, J.K.K. Nattraja College of Pharmacy, Komarapalayam- 638 183, India
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Vargas Vargas RA, Varela Millán JM, Fajardo Bonilla E. Renin-angiotensin system: Basic and clinical aspects-A general perspective. ENDOCRINOLOGIA, DIABETES Y NUTRICION 2022; 69:52-62. [PMID: 35232560 PMCID: PMC8882059 DOI: 10.1016/j.endien.2022.01.005] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 05/10/2021] [Indexed: 12/21/2022]
Abstract
The renin–angiotensin system (RAS) is one of the most complex hormonal regulatory systems, involving several organs that interact to regulate multiple body functions. The study of this system initially focused on investigating its role in the regulation of both cardiovascular function and related pathologies. From this approach, pharmacological strategies were developed for the treatment of cardiovascular diseases. However, new findings in recent decades have suggested that the RAS is much more complex and comprises two subsystems, the classic RAS and an alternative RAS, with antagonistic effects that are usually in equilibrium. The classic system is involved in pathologies where inflammatory, hypertrophic and fibrotic phenomena are common and is related to the development of chronic diseases that affect various body systems. This understanding has been reinforced by the evidence that local renin–angiotensin systems exist in many tissue types and by the role of the RAS in the spread and severity of COVID-19 infection, where it was discovered that viral entry into cells of the respiratory system is accomplished through binding to angiotensin-converting enzyme 2, which is present in the alveolar epithelium and is overexpressed in patients with chronic cardiometabolic diseases. In this narrative review, preclinical and clinical aspects of the RAS are presented and topics for future research are discussed some aspects are raised that should be clarified in the future and that call for further investigation of this system.
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Affiliation(s)
- Rafael Antonio Vargas Vargas
- Universidad Militar Nueva Granada, Facultad de medicina, Bogotá, Colombia; Universidad Santo Tomás, Maestría en actividad física para la salud, Bogotá, Colombia.
| | - Jesús María Varela Millán
- Universidad Militar Nueva Granada, Facultad de medicina, Bogotá, Colombia; Universidad Santo Tomás, Maestría en actividad física para la salud, Bogotá, Colombia
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25
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Wiegel RE, Fares DA, Willemsen SP, Steegers EA, Danser AJ, Steegers-Theunissen RP. First-trimester maternal renin-angiotensin-aldosterone system activation and fetal growth and birth weight: The Rotterdam Periconceptional Cohort. Reprod Biomed Online 2022; 44:1110-1122. [DOI: 10.1016/j.rbmo.2021.12.020] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2021] [Revised: 12/14/2021] [Accepted: 12/15/2021] [Indexed: 10/19/2022]
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26
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Improta-Caria AC, Aras MG, Nascimento L, De Sousa RAL, Aras-Júnior R, Souza BSDF. MicroRNAs Regulating Renin-Angiotensin-Aldosterone System, Sympathetic Nervous System and Left Ventricular Hypertrophy in Systemic Arterial Hypertension. Biomolecules 2021; 11:biom11121771. [PMID: 34944415 PMCID: PMC8698399 DOI: 10.3390/biom11121771] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2021] [Revised: 10/25/2021] [Accepted: 10/31/2021] [Indexed: 12/21/2022] Open
Abstract
MicroRNAs are small non-coding RNAs that regulate gene and protein expression. MicroRNAs also regulate several cellular processes such as proliferation, differentiation, cell cycle, apoptosis, among others. In this context, they play important roles in the human body and in the pathogenesis of diseases such as cancer, diabetes, obesity and hypertension. In hypertension, microRNAs act on the renin-angiotensin-aldosterone system, sympathetic nervous system and left ventricular hypertrophy, however the signaling pathways that interact in these processes and are regulated by microRNAs inducing hypertension and the worsening of the disease still need to be elucidated. Thus, the aim of this review is to analyze the pattern of expression of microRNAs in these processes and the possible associated signaling pathways.
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Affiliation(s)
- Alex Cleber Improta-Caria
- Post-Graduate Program in Medicine and Health, Faculty of Medicine, Federal University of Bahia, Salvador 40110-100, Brazil;
- Department of Physical Education in Cardiology of the State of Bahia, Brazilian Society of Cardiology, Salvador 41170-130, Brazil
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador 41253-190, Brazil
- Correspondence: (A.C.I.-C.); (B.S.d.F.S.)
| | - Marcela Gordilho Aras
- Faculty of Medicine, Federal University of Bahia, Salvador 40110-100, Brazil; (M.G.A.); (L.N.)
| | - Luca Nascimento
- Faculty of Medicine, Federal University of Bahia, Salvador 40110-100, Brazil; (M.G.A.); (L.N.)
| | | | - Roque Aras-Júnior
- Post-Graduate Program in Medicine and Health, Faculty of Medicine, Federal University of Bahia, Salvador 40110-100, Brazil;
- Faculty of Medicine, Federal University of Bahia, Salvador 40110-100, Brazil; (M.G.A.); (L.N.)
| | - Bruno Solano de Freitas Souza
- Center for Biotechnology and Cell Therapy, São Rafael Hospital, Salvador 41253-190, Brazil
- D’Or Institute for Research and Education (IDOR), Salvador 22281-100, Brazil
- Gonçalo Moniz Institute, Oswaldo Cruz Foundation (FIOCRUZ), Salvador 40296-710, Brazil
- Correspondence: (A.C.I.-C.); (B.S.d.F.S.)
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27
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Vargas Vargas RA, Varela Millán JM, Fajardo Bonilla E. Renin-angiotensin system: Basic and clinical aspects-A general perspective. ACTA ACUST UNITED AC 2021; 69:52-62. [PMID: 34723133 PMCID: PMC8547789 DOI: 10.1016/j.endinu.2021.05.012] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2020] [Accepted: 05/10/2021] [Indexed: 12/22/2022]
Abstract
The renin–angiotensin system (RAS) is one of the most complex hormonal regulatory systems, involving several organs that interact to regulate multiple body functions. The study of this system initially focused on investigating its role in the regulation of both cardiovascular function and related pathologies. From this approach, pharmacological strategies were developed for the treatment of cardiovascular diseases. However, new findings in recent decades have suggested that the RAS is much more complex and comprises two subsystems, the classic RAS and an alternative RAS, with antagonistic effects that are usually in equilibrium. The classic system is involved in pathologies where inflammatory, hypertrophic and fibrotic phenomena are common and is related to the development of chronic diseases that affect various body systems. This understanding has been reinforced by the evidence that local renin–angiotensin systems exist in many tissue types and by the role of the RAS in the spread and severity of COVID-19 infection, where it was discovered that viral entry into cells of the respiratory system is accomplished through binding to angiotensin-converting enzyme 2, which is present in the alveolar epithelium and is overexpressed in patients with chronic cardiometabolic diseases. In this narrative review, preclinical and clinical aspects of the RAS are presented and topics for future research are discussed some aspects are raised that should be clarified in the future and that call for further investigation of this system.
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Affiliation(s)
- Rafael Antonio Vargas Vargas
- Universidad Militar Nueva Granada, Facultad de medicina, Bogotá, Colombia.,Universidad Santo Tomás, Maestría en actividad física para la salud, Bogotá, Colombia
| | - Jesús María Varela Millán
- Universidad Militar Nueva Granada, Facultad de medicina, Bogotá, Colombia.,Universidad Santo Tomás, Maestría en actividad física para la salud, Bogotá, Colombia
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28
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Taavo M, Rundgren M, Frykholm P, Larsson A, Franzén S, Vargmar K, Valarcher JF, DiBona GF, Frithiof R. Role of Renal Sympathetic Nerve Activity in Volatile Anesthesia's Effect on Renal Excretory Function. FUNCTION (OXFORD, ENGLAND) 2021; 2:zqab042. [PMID: 35330795 PMCID: PMC8788708 DOI: 10.1093/function/zqab042] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 06/01/2021] [Revised: 07/18/2021] [Accepted: 08/16/2021] [Indexed: 01/07/2023]
Abstract
Regulation of fluid balance is pivotal during surgery and anesthesia and affects patient morbidity, mortality, and hospital length of stay. Retention of sodium and water is known to occur during surgery but the mechanisms are poorly defined. In this study, we explore how the volatile anesthetic sevoflurane influences renal function by affecting renal sympathetic nerve activity (RSNA). Our results demonstrate that sevoflurane induces renal sodium and water retention during pediatric anesthesia in association with elevated plasma concentration of renin but not arginine-vasopressin. The mechanisms are further explored in conscious and anesthetized ewes where we show that RSNA is increased by sevoflurane compared with when conscious. This is accompanied by renal sodium and water retention and decreased renal blood flow (RBF). Finally, we demonstrate that renal denervation normalizes renal excretory function and improves RBF during sevoflurane anesthesia in sheep. Taken together, this study describes a novel role of the renal sympathetic nerves in regulating renal function and blood flow during sevoflurane anesthesia.
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Affiliation(s)
| | - Mats Rundgren
- Department of Physiology and Pharmacology, Karolinska Institute, Stockholm, Sweden
| | - Peter Frykholm
- Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden
| | - Anders Larsson
- Department of Medical Sciences and Clinical Chemistry, Uppsala University, Uppsala, Sweden
| | - Stephanie Franzén
- Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden
| | - Karin Vargmar
- Department of Biomedical Sciences and Veterinary Public Health, Section of Pathology, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Jean F Valarcher
- Department of Clinical Sciences, Division of Ruminant Medicine, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - Gerald F DiBona
- Carver College of Medicine, University of Iowa, Iowa, IA, USA
| | - Robert Frithiof
- Department of Surgical Sciences, Anesthesiology and Intensive Care, Uppsala University, Uppsala, Sweden
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29
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Eckenstaler R, Sandori J, Gekle M, Benndorf RA. Angiotensin II receptor type 1 - An update on structure, expression and pathology. Biochem Pharmacol 2021; 192:114673. [PMID: 34252409 DOI: 10.1016/j.bcp.2021.114673] [Citation(s) in RCA: 38] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2021] [Revised: 07/02/2021] [Accepted: 07/06/2021] [Indexed: 12/12/2022]
Abstract
The AT1 receptor, a major effector of the renin-angiotensin system, has been extensively studied in the context of cardiovascular and renal disease. Moreover, angiotensin receptor blockers, sartans, are among the most frequently prescribed drugs for the treatment of hypertension, chronic heart failure and chronic kidney disease. However, precise molecular insights into the structure of this important drug target have not been available until recently. In this context, seminal studies have now revealed exciting new insights into the structure and biased signaling of the receptor and may thus foster the development of novel therapeutic approaches to enhance the efficacy of pharmacological angiotensin receptor antagonism or to enable therapeutic induction of biased receptor activity. In this review, we will therefore highlight these and other seminal publications to summarize the current understanding of the tertiary structure, ligand binding properties and downstream signal transduction of the AT1 receptor.
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Affiliation(s)
| | - Jana Sandori
- Institute of Pharmacy, Martin-Luther-University, Halle, Germany
| | - Michael Gekle
- Julius-Bernstein-Institute of Physiology, Martin-Luther-University, Halle, Germany
| | - Ralf A Benndorf
- Institute of Pharmacy, Martin-Luther-University, Halle, Germany.
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30
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Kono K, Fujii H, Watanabe K, Goto S, Nishi S. Relationship between parathyroid hormone and renin-angiotensin-aldosterone system in hemodialysis patients with secondary hyperparathyroidism. J Bone Miner Metab 2021; 39:230-236. [PMID: 32920706 DOI: 10.1007/s00774-020-01139-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 08/05/2020] [Indexed: 10/23/2022]
Abstract
INTRODUCTION Hyperparathyroidism (HPT) is associated with mortality and cardiovascular disease (CVD) in dialysis patients. However, its mechanism is still unclear. It is suspected that parathyroid hormone (PTH) is associated with the renin-angiotensin-aldosterone system (RAAS) as a possible mechanism. Thus, we examined their hormonal interaction in hemodialysis patients with secondary HPT. MATERIALS AND METHODS Seventeen hemodialysis patients with HPT were included. All patients underwent total parathyroidectomy (PTx). Serum intact PTH (iPTH), calcium and phosphate levels, plasma renin activity (PRA), and plasma aldosterone levels (ALD) were measured pre- and post-PTx. RESULTS Pre-serum iPTH tended to be correlated with pre-PRA and were significantly correlated with pre-ALD (pre-PRA: r = 0.44, p = 0.07, pre-ALD: r = 0.49, p < 0.05). With the reduction in serum iPTH after PTx, PRA and ALD significantly decreased after PTx. Additionally, the change in serum iPTH tended to be correlated with the changes in PRA and ALD (PRA; r = 0.46, p = 0.05, ALD; r = 0.45, p = 0.06). CONCLUSION Our results suggest that PTH could be interrelated with RAAS in hemodialysis patients with secondary HPT.
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Affiliation(s)
- Keiji Kono
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan.
| | - Hideki Fujii
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Kentaro Watanabe
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Shunsuke Goto
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
| | - Shinichi Nishi
- Division of Nephrology and Kidney Center, Kobe University Graduate School of Medicine, 7-5-2, Kusunoki-cho, Chuo-ku, Kobe, Hyogo, 650-0017, Japan
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Curnow AC, Gonsalez SR, Gogulamudi VR, Visniauskas B, Simon EE, Gonzalez AA, Majid DSA, Lara LS, Prieto MC. Low Nitric Oxide Bioavailability Increases Renin Production in the Collecting Duct. Front Physiol 2020; 11:559341. [PMID: 33281610 PMCID: PMC7705222 DOI: 10.3389/fphys.2020.559341] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2020] [Accepted: 10/21/2020] [Indexed: 12/14/2022] Open
Abstract
In the kidney, the stimulation of renin production by the collecting duct (CD-renin) contributes to the development of hypertension. The CD is a major nephron segment for the synthesis of nitric oxide (NO), and low NO bioavailability in the renal medulla is associated with hypertension. However, it is unknown whether NO regulates renin production in the CD. To test the hypothesis that low intrarenal NO levels stimulate the production of CD-renin, we first examined renin expression in the distal nephron segments of CD-eNOS deficient mice. In these mice, specific CD-renin immunoreactivity was increased compared to wild-type littermates; however, juxtaglomerular (JG) renin was not altered. To further assess the intracellular mechanisms involved, we then treated M-1 cells with either 1 mM L-NAME (L-arginine analog), an inhibitor of NO synthase activity, or 1 mM NONOate, a NO donor. Both treatments increased intracellular renin protein levels in M-1 cells. However, only the inhibition of NOS with L-NAME stimulated renin synthesis and secretion as reflected by the increase in Ren1C transcript and renin protein levels in the extracellular media, respectively. In addition, NONOate induced a fast mobilization of cGMP and intracellular renin accumulation. These response was partially prevented by guanylyl cyclase inhibition with ODQ (1H-[1,2,4] oxadiazolo[4,3-a]quinoxalin-1]. Accumulation of intracellular renin was blocked by protein kinase G (PKG) and protein kinase C (PKC) inhibitors. Our data indicate that low NO bioavailability increases CD-renin synthesis and secretion, which may contribute to the activation of intrarenal renin angiotensin system.
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Affiliation(s)
- Andrew C. Curnow
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Sabrina R. Gonsalez
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | | | - Bruna Visniauskas
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
| | - Eric E. Simon
- Department of Medicine, Tulane University School of Medicine, New Orleans, LA, United States
| | - Alexis A. Gonzalez
- Instituto de Química, Pontificia Universidad Católica de Valparaíso, Valparaíso, Chile
| | - Dewan S. A. Majid
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
- Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, United States
| | - Lucienne S. Lara
- Instituto de Ciências Biomédicas, Universidade Federal do Rio de Janeiro, Rio de Janeiro, Brazil
| | - Minolfa C. Prieto
- Department of Physiology, Tulane University School of Medicine, New Orleans, LA, United States
- Hypertension and Renal Center of Excellence, Tulane University School of Medicine, New Orleans, LA, United States
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Abstract
The recent demonstration of the significant reduction in mortality in patients with septic shock treated with adjunctive glucocorticoids combined with fludrocortisone and the effectiveness of angiotensin II in treating vasodilatory shock have renewed interest in the role of the mineralocorticoid axis in critical illness. Glucocorticoids have variable interactions at the mineralocorticoid receptor. Similarly, mineralocorticoid receptor-aldosterone interactions differ from mineralocorticoid receptor-glucocorticoid interactions and predicate receptor-ligand interactions that differ with respect to cellular effects. Hyperreninemic hypoaldosteronism or selective hypoaldosteronism, an impaired adrenal response to increasing renin levels, occurs in a subgroup of hemodynamically unstable critically ill patients. The suggestion is that there is a defect at the level of the adrenal zona glomerulosa associated with a high mortality rate that may represent an adaptive response aimed at increasing cortisol levels. Furthermore, cross-talk exists between angiotensin II and aldosterone, which needs to be considered when employing therapeutic strategies.
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Duan C, do Nascimento NC, Calve S, Cox A, Sivasankar MP. Restricted Water Intake Adversely Affects Rat Vocal Fold Biology. Laryngoscope 2020; 131:839-845. [PMID: 32658340 DOI: 10.1002/lary.28881] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/16/2020] [Revised: 05/14/2020] [Accepted: 05/26/2020] [Indexed: 11/10/2022]
Abstract
OBJECTIVES A holistic understanding of the many ways that systemic dehydration affects vocal fold biology is still evolving. There are also myriad physiologically relevant methodologies to induce systemic dehydration. To untangle the effects of systemic dehydration on vocal fold biology, we need to utilize realistic, clinically translatable paradigms of systemic dehydration in lab animals. Restricted access to water accommodates clinical translation. We investigated whether systemic dehydration via reduced water intake would negatively affect vocal fold biology. STUDY DESIGN Prospective, in vivo study design. METHODS Male Sprague Dawley rats (N = 13) were provided 4 mL/100 g of water/day for 5 days, whereas male control rats (N = 8) were given ad lib access to water. Following euthanasia, tissues were processed for histological staining, gene expression, and protein assays. RESULTS Renin gene expression level in kidneys increased significantly (P ≤ .05), validating dehydration. Dehydration induced by restricted water access downregulated the gene expression of interleukin-1α and desmoglein-1 (P ≤ .05). Hyaluronidase-2 gene expression increased after dehydration (P ≤ .05). The protein level of desmoglein-1 decreased after dehydration (P ≤ .05). Histological analyses suggested decreased hyaluronan (P ≤ .05) in the water-restricted rat vocal fold. CONCLUSION Reduced daily water intake for just 5 days impairs vocal fold biology by disrupting inflammatory cytokine release, reducing plasma membrane integrity, and disrupting the hyaluronan network. This is the first study investigating the dehydrating effects of restricted water intake on vocal fold tissue in an in vivo model. LEVEL OF EVIDENCE NA (prospective animal study). Laryngoscope, 131:839-845, 2021.
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Affiliation(s)
- Chenwei Duan
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, U.S.A.,Department of Speech, Language, and Hearing Sciences, Purdue University, West Lafayette, Indiana, U.S.A
| | - Naila Cannes do Nascimento
- Department of Speech, Language, and Hearing Sciences, Purdue University, West Lafayette, Indiana, U.S.A.,Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana, U.S.A
| | - Sarah Calve
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, U.S.A.,Department of Mechanical Engineering, University of Colorado-Boulder, Boulder, Colorado, U.S.A
| | - Abigail Cox
- Department of Comparative Pathobiology, Purdue University, West Lafayette, Indiana, U.S.A
| | - M Preeti Sivasankar
- Weldon School of Biomedical Engineering, Purdue University, West Lafayette, Indiana, U.S.A.,Department of Speech, Language, and Hearing Sciences, Purdue University, West Lafayette, Indiana, U.S.A
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Rifaioglu AS, Nalbat E, Atalay V, Martin MJ, Cetin-Atalay R, Doğan T. DEEPScreen: high performance drug-target interaction prediction with convolutional neural networks using 2-D structural compound representations. Chem Sci 2020; 11:2531-2557. [PMID: 33209251 PMCID: PMC7643205 DOI: 10.1039/c9sc03414e] [Citation(s) in RCA: 123] [Impact Index Per Article: 24.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2019] [Accepted: 01/05/2020] [Indexed: 12/12/2022] Open
Abstract
The identification of physical interactions between drug candidate compounds and target biomolecules is an important process in drug discovery. Since conventional screening procedures are expensive and time consuming, computational approaches are employed to provide aid by automatically predicting novel drug-target interactions (DTIs). In this study, we propose a large-scale DTI prediction system, DEEPScreen, for early stage drug discovery, using deep convolutional neural networks. One of the main advantages of DEEPScreen is employing readily available 2-D structural representations of compounds at the input level instead of conventional descriptors that display limited performance. DEEPScreen learns complex features inherently from the 2-D representations, thus producing highly accurate predictions. The DEEPScreen system was trained for 704 target proteins (using curated bioactivity data) and finalized with rigorous hyper-parameter optimization tests. We compared the performance of DEEPScreen against the state-of-the-art on multiple benchmark datasets to indicate the effectiveness of the proposed approach and verified selected novel predictions through molecular docking analysis and literature-based validation. Finally, JAK proteins that were predicted by DEEPScreen as new targets of a well-known drug cladribine were experimentally demonstrated in vitro on cancer cells through STAT3 phosphorylation, which is the downstream effector protein. The DEEPScreen system can be exploited in the fields of drug discovery and repurposing for in silico screening of the chemogenomic space, to provide novel DTIs which can be experimentally pursued. The source code, trained "ready-to-use" prediction models, all datasets and the results of this study are available at ; https://github.com/cansyl/DEEPscreen.
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Affiliation(s)
- Ahmet Sureyya Rifaioglu
- Department of Computer Engineering , METU , Ankara , 06800 , Turkey . ; Tel: +903122105576
- Department of Computer Engineering , İskenderun Technical University , Hatay , 31200 , Turkey
- KanSiL , Department of Health Informatics , Graduate School of Informatics , METU , Ankara , 06800 , Turkey
| | - Esra Nalbat
- KanSiL , Department of Health Informatics , Graduate School of Informatics , METU , Ankara , 06800 , Turkey
| | - Volkan Atalay
- Department of Computer Engineering , METU , Ankara , 06800 , Turkey . ; Tel: +903122105576
- KanSiL , Department of Health Informatics , Graduate School of Informatics , METU , Ankara , 06800 , Turkey
| | - Maria Jesus Martin
- European Molecular Biology Laboratory , European Bioinformatics Institute (EMBL-EBI) , Hinxton , Cambridge , CB10 1SD , UK
| | - Rengul Cetin-Atalay
- KanSiL , Department of Health Informatics , Graduate School of Informatics , METU , Ankara , 06800 , Turkey
- Section of Pulmonary and Critical Care Medicine , The University of Chicago , Chicago , IL 60637 , USA
| | - Tunca Doğan
- Department of Computer Engineering , Hacettepe University , Ankara , 06800 , Turkey . ; Tel: +903122977193/117
- Institute of Informatics , Hacettepe University , Ankara , 06800 , Turkey
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McArdle Z, Pontes RB, Yao ST, Lankadeva YR, Singh RR, Hood SG, Schlaich MP, May CN, Booth LC. Blunted diuretic and natriuretic responses to acute sodium loading early after catheter-based renal denervation in normotensive sheep. Am J Physiol Regul Integr Comp Physiol 2019; 317:R319-R327. [DOI: 10.1152/ajpregu.00228.2018] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Catheter-based renal denervation (RDN) was introduced as a treatment for resistant hypertension. There remain critical questions regarding the physiological mechanisms underlying the hypotensive effects of catheter-based RDN. Previous studies indicate that surgical denervation reduces renin and the natriuretic response to saline loading; however, the effects on these variables of catheter-based RDN, which does not yield complete denervation, are largely unknown. The aim of this study was to investigate the effects of catheter-based RDN on glomerular-associated renin and regulation of fluid and sodium homeostasis in response to physiological challenges. First, immunohistochemical staining for renin was performed in normotensive sheep ( n = 6) and sheep at 1 wk ( n = 6), 5.5 mo ( n = 5), and 11 mo ( n = 5) after unilateral RDN using the same catheter used in patients (Symplicity). Following catheter-based RDN (1 wk), renin-positive glomeruli were significantly reduced compared with sham animals ( P < 0.005). This was sustained until 5.5 mo postdenervation. To determine whether the reduction in renin after 1 wk had physiological effects, in a separate cohort, Merino ewes were administered high and low saline loads before and 1 wk after bilateral RDN ( n = 9) or sham procedure ( n = 8). After RDN (1 wk), the diuretic response to a low saline load was significantly reduced ( P < 0.05), and both the diuretic and natriuretic responses to a high saline load were significantly attenuated ( P < 0.05). In conclusion, these findings indicate that catheter-based RDN acutely alters the ability of the kidney to regulate fluid and electrolyte balance. Further studies are required to determine the long-term effects of catheter-based RDN on renal sodium and water homeostasis.
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Affiliation(s)
- Zoe McArdle
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
- Cardiovascular Program, Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Melbourne, Australia
| | - Roberto B. Pontes
- Cardiovascular Division, Department of Physiology, Federal University of São Paulo, São Paulo, Brazil
| | - Song T. Yao
- Faculty of Medicine, Dentistry and Health Sciences, Florey Department of Neuroscience and Mental Health, University of Melbourne, Melbourne, Australia
| | - Yugeesh R. Lankadeva
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
| | - Reetu R. Singh
- Cardiovascular Program, Monash Biomedicine Discovery Institute and Department of Physiology, Monash University, Melbourne, Australia
| | - Sally G. Hood
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
| | - Markus P. Schlaich
- Dobney Hypertension Centre, School of Medicine-Royal Perth Hospital Unit, University of Western Australia, Perth, Australia
| | - Clive N. May
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
| | - Lindsea C. Booth
- Florey Institute of Neuroscience and Mental Health, University of Melbourne, Parkville, Victoria, Australia
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Hirunpattarasilp C, Attwell D, Freitas F. The role of pericytes in brain disorders: from the periphery to the brain. J Neurochem 2019; 150:648-665. [PMID: 31106417 DOI: 10.1111/jnc.14725] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2019] [Revised: 03/15/2019] [Accepted: 05/15/2019] [Indexed: 12/13/2022]
Abstract
It is becoming increasingly apparent that disorders of the brain microvasculature contribute to many neurological disorders. In recent years it has become clear that a major player in these events is the capillary pericyte which, in the brain, is now known to control the blood-brain barrier, regulate blood flow, influence immune cell entry and be crucial for angiogenesis. In this review we consider the under-explored possibility that peripheral diseases which affect the microvasculature, such as hypertension, kidney disease and diabetes, produce central nervous system (CNS) dysfunction by mechanisms affecting capillary pericytes within the CNS. We highlight how cellular messengers produced peripherally can act via signalling pathways within CNS pericytes to reshape blood vessels, restrict blood flow or compromise blood-brain barrier function, thus causing neuronal dysfunction. Increased understanding of how renin-angiotensin, Rho-kinase and PDGFRβ signalling affect CNS pericytes may suggest novel therapeutic approaches to reducing the CNS effects of peripheral disorders.
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Affiliation(s)
- Chanawee Hirunpattarasilp
- Department of Neuroscience, Andrew Huxley Building, University College London, Physiology & Pharmacology, Gower Street, London, UK
| | - David Attwell
- Department of Neuroscience, Andrew Huxley Building, University College London, Physiology & Pharmacology, Gower Street, London, UK
| | - Felipe Freitas
- Department of Neuroscience, Andrew Huxley Building, University College London, Physiology & Pharmacology, Gower Street, London, UK
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Minocha E, Chaturvedi CP, Nityanand S. Renogenic characterization and in vitro differentiation of rat amniotic fluid stem cells into renal proximal tubular- and juxtaglomerular-like cells. In Vitro Cell Dev Biol Anim 2019; 55:138-147. [PMID: 30645697 DOI: 10.1007/s11626-018-00315-2] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2018] [Accepted: 12/16/2018] [Indexed: 12/31/2022]
Abstract
The aim of the present study was to investigate the renogenic characteristics of amniotic fluid stem cells (AFSCs) and to evaluate their in vitro differentiation potential into renal proximal tubular-like cells and juxtaglomerular-like cells. We culture expanded AFSCs derived from rat amniotic fluid. The AFSCs grew as adherent spindle-shaped cells and expressed mesenchymal markers CD73, CD90, and CD105 as well as renal progenitor markers WT1, PAX2, SIX2, SALL1, and CITED1. AFSCs exhibited an in vitro differentiation potential into renal proximal tubular epithelial-like cells, as shown by the upregulation of expression of proximal tubular cell-specific genes like AQP1, CD13, PEPT1, GLUT5, OAT1, and OCT1. AFSCs could also be differentiated into juxtaglomerular-like cells as demonstrated by the expression of renin and α-SMA. The AFSCs also expressed pluripotency markers OCT4, NANOG, and SOX2 and could be induced into embryoid bodies with differentiation into all the three germ layers, highlighting the pluripotent nature of these cells. Our results show that amniotic fluid contains a population of primitive stem cells that express renal-progenitor markers and also possess the propensity to differentiate into two renal lineage cell types and, thus, may have a therapeutic potential in renal regenerative medicine.
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Affiliation(s)
- Ekta Minocha
- Stem Cell Research Facility, Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Raebareli Road, Lucknow, UP, 226014, India
| | - Chandra Prakash Chaturvedi
- Stem Cell Research Facility, Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Raebareli Road, Lucknow, UP, 226014, India
| | - Soniya Nityanand
- Stem Cell Research Facility, Department of Hematology, Sanjay Gandhi Postgraduate Institute of Medical Sciences (SGPGIMS), Raebareli Road, Lucknow, UP, 226014, India.
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Sharma N, Anders HJ, Gaikwad AB. Fiend and friend in the renin angiotensin system: An insight on acute kidney injury. Biomed Pharmacother 2018; 110:764-774. [PMID: 30554115 DOI: 10.1016/j.biopha.2018.12.018] [Citation(s) in RCA: 62] [Impact Index Per Article: 8.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2018] [Revised: 12/05/2018] [Accepted: 12/05/2018] [Indexed: 02/06/2023] Open
Abstract
Besides assisting the maintenance of blood pressure and sodium homeostasis, the renin-angiotensin system (RAS) plays a pivotal role in pathogenesis of acute kidney injury (AKI). The RAS is equipped with two arms i) the pressor arm composed of Angiotensin II (Ang II)/Angiotensin converting enzyme (ACE)/Angiotensin II type 1 receptor (AT1R) also called conventional RAS, and ii) the depressor arm consisting of Angiotensin (1-7) (Ang 1-7)/Angiotensin converting enzyme 2 (ACE2)/MasR known as non-conventional RAS. Activation of conventional RAS triggers oxidative stress, inflammatory, hypertrophic, apoptotic, and pro-fibrotic signaling cascades which promote AKI. The preclinical and clinical studies have reported beneficial as well as deleterious effects of RAS blockage either by angiotensin receptor blocker or ACE inhibitor in AKI. On the contrary, the depressor arm opposes the conventional RAS, has beneficial effects on the kidney but has been less explored in pathogenesis of AKI. This review focuses on significance of RAS in pathogenesis of AKI and provides better understanding of novel and possible therapeutic approaches to combat AKI.
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Affiliation(s)
- Nisha Sharma
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Rajasthan 333 031, India
| | - Hans-Joachim Anders
- Division of Nephrology, Department of Internal Medicine IV, University Hospital of the Ludwig Maximilians University Munich, 80336 Munich, Germany
| | - Anil Bhanudas Gaikwad
- Laboratory of Molecular Pharmacology, Department of Pharmacy, Birla Institute of Technology and Science, Pilani, Pilani Campus, Rajasthan 333 031, India.
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Hoffmann S, Mullins L, Buckley C, Rider S, Mullins J. Investigating the RAS can be a fishy business: interdisciplinary opportunities using Zebrafish. Clin Sci (Lond) 2018; 132:2469-2481. [PMID: 30518571 PMCID: PMC6279434 DOI: 10.1042/cs20180721] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2018] [Revised: 11/02/2018] [Accepted: 11/19/2018] [Indexed: 02/06/2023]
Abstract
The renin-angiotensin system (RAS) is highly conserved, and components of the RAS are present in all vertebrates to some degree. Although the RAS has been studied since the discovery of renin, its biological role continues to broaden with the identification and characterization of new peptides. The evolutionarily distant zebrafish is a remarkable model for studying the kidney due to its genetic tractability and accessibility for in vivo imaging. The zebrafish pronephros is an especially useful kidney model due to its structural simplicity yet complex functionality, including capacity for glomerular and tubular filtration. Both the pronephros and mesonephros contain renin-expressing perivascular cells, which respond to RAS inhibition, making the zebrafish an excellent model for studying the RAS. This review summarizes the physiological and genetic tools currently available for studying the zebrafish kidney with regards to functionality of the RAS, using novel imaging techniques such as SPIM microscopy coupled with targeted single cell ablation and synthesis of vasoactive RAS peptides.
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Affiliation(s)
- Scott Hoffmann
- University of Edinburgh/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of Edinburgh, 47, Little France Crescent, Edinburgh EH16 4TJ, U.K
| | - Linda Mullins
- University of Edinburgh/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of Edinburgh, 47, Little France Crescent, Edinburgh EH16 4TJ, U.K
| | - Charlotte Buckley
- University of Edinburgh/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of Edinburgh, 47, Little France Crescent, Edinburgh EH16 4TJ, U.K
| | - Sebastien Rider
- University of Edinburgh/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of Edinburgh, 47, Little France Crescent, Edinburgh EH16 4TJ, U.K
| | - John Mullins
- University of Edinburgh/BHF Centre for Cardiovascular Science, Queen's Medical Research Institute, The University of Edinburgh, 47, Little France Crescent, Edinburgh EH16 4TJ, U.K.
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Hommos MS, Schwartz GL. Clinical value of plasma renin activity and aldosterone concentration in the evaluation of secondary hypertension, a case of reninoma. ACTA ACUST UNITED AC 2018; 12:641-643. [DOI: 10.1016/j.jash.2018.06.001] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2018] [Accepted: 06/01/2018] [Indexed: 11/26/2022]
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Levy B, Fritz C, Tahon E, Jacquot A, Auchet T, Kimmoun A. Vasoplegia treatments: the past, the present, and the future. Crit Care 2018; 22:52. [PMID: 29486781 PMCID: PMC6389278 DOI: 10.1186/s13054-018-1967-3] [Citation(s) in RCA: 136] [Impact Index Per Article: 19.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2017] [Accepted: 01/26/2018] [Indexed: 12/20/2022] Open
Abstract
Vasoplegia is a ubiquitous phenomenon in all advanced shock states, including septic, cardiogenic, hemorrhagic, and anaphylactic shock. Its pathophysiology is complex, involving various mechanisms in vascular smooth muscle cells such as G protein-coupled receptor desensitization (adrenoceptors, vasopressin 1 receptors, angiotensin type 1 receptors), alteration of second messenger pathways, critical illness-related corticosteroid insufficiency, and increased production of nitric oxide. This review, based on a critical appraisal of the literature, discusses the main current treatments and future approaches. Our improved understanding of these mechanisms is progressively changing our therapeutic approach to vasoplegia from a standardized to a personalized multimodal treatment with the prescription of several vasopressors. While norepinephrine is confirmed as first line therapy for the treatment of vasoplegia, the latest Surviving Sepsis Campaign guidelines also consider that the best therapeutic management of vascular hyporesponsiveness to vasopressors could be a combination of multiple vasopressors, including norepinephrine and early prescription of vasopressin. This new approach is seemingly justified by the need to limit adrenoceptor desensitization as well as sympathetic overactivation given its subsequent deleterious impacts on hemodynamics and inflammation. Finally, based on new pathophysiological data, two potential drugs, selepressin and angiotensin II, are currently being evaluated.
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Affiliation(s)
- Bruno Levy
- CHRU Nancy, Service de Réanimation Médicale Brabois, Pôle Cardiovasculaire et Réanimation Médicale, Hôpital Brabois, Vandoeuvre les Nancy, France
- INSERM U 1116, Groupe Choc, Equipe 2, Faculté de Médecine, Vandoeuvre les Nancy, France
- Université de Lorraine, Faculté de Médecine, Nancy, France
| | - Caroline Fritz
- CHRU Nancy, Service de Réanimation Médicale Brabois, Pôle Cardiovasculaire et Réanimation Médicale, Hôpital Brabois, Vandoeuvre les Nancy, France
- INSERM U 1116, Groupe Choc, Equipe 2, Faculté de Médecine, Vandoeuvre les Nancy, France
- Université de Lorraine, Faculté de Médecine, Nancy, France
| | - Elsa Tahon
- CHRU Nancy, Service de Réanimation Médicale Brabois, Pôle Cardiovasculaire et Réanimation Médicale, Hôpital Brabois, Vandoeuvre les Nancy, France
| | - Audrey Jacquot
- CHRU Nancy, Service de Réanimation Médicale Brabois, Pôle Cardiovasculaire et Réanimation Médicale, Hôpital Brabois, Vandoeuvre les Nancy, France
| | - Thomas Auchet
- CHRU Nancy, Service de Réanimation Médicale Brabois, Pôle Cardiovasculaire et Réanimation Médicale, Hôpital Brabois, Vandoeuvre les Nancy, France
| | - Antoine Kimmoun
- CHRU Nancy, Service de Réanimation Médicale Brabois, Pôle Cardiovasculaire et Réanimation Médicale, Hôpital Brabois, Vandoeuvre les Nancy, France
- INSERM U 1116, Groupe Choc, Equipe 2, Faculté de Médecine, Vandoeuvre les Nancy, France
- Université de Lorraine, Faculté de Médecine, Nancy, France
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Holappa M, Vapaatalo H, Vaajanen A. Many Faces of Renin-angiotensin System - Focus on Eye. Open Ophthalmol J 2017; 11:122-142. [PMID: 28761566 PMCID: PMC5510558 DOI: 10.2174/1874364101711010122] [Citation(s) in RCA: 93] [Impact Index Per Article: 11.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2017] [Revised: 05/17/2017] [Accepted: 05/25/2017] [Indexed: 12/18/2022] Open
Abstract
The renin-angiotensin system (RAS), that is known for its role in the regulation of blood pressure as well as in fluid and electrolyte homeostasis, comprises dozens of angiotensin peptides and peptidases and at least six receptors. Six central components constitute the two main axes of the RAS cascade. Angiotensin (1-7), an angiotensin converting enzyme 2 and Mas receptor axis (ACE2-Ang(1-7)-MasR) counterbalances the harmful effects of the angiotensin II, angiotensin converting enzyme 1 and angiotensin II type 1 receptor axis (ACE1-AngII-AT1R) Whereas systemic RAS is an important factor in blood pressure regulation, tissue-specific regulatory system, responsible for long term regional changes, that has been found in various organs. In other words, RAS is not only endocrine but also complicated autocrine system. The human eye has its own intraocular RAS that is present e.g. in the structures involved in aqueous humor dynamics. Local RAS may thus be a target in the development of new anti-glaucomatous drugs. In this review, we first describe the systemic RAS cascade and then the local ocular RAS especially in the anterior part of the eye.
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Affiliation(s)
- Mervi Holappa
- BioMediTech, University of Tampere, Tampere, Finland
| | - Heikki Vapaatalo
- Medical Faculty, Department of Pharmacology, University of Helsinki, 00014 Helsinki, Finland
| | - Anu Vaajanen
- Department of Ophthalmology, Tampere University Hospital, Tampere, Finland.,SILK, Department of Ophthalmology, School of Medicine, University of Tampere, Tampere, Finland
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Asoodeh A, Homayouni-Tabrizi M, Shabestarian H, Emtenani S, Emtenani S. Biochemical characterization of a novel antioxidant and angiotensin I-converting enzyme inhibitory peptide from Struthio camelus egg white protein hydrolysis. J Food Drug Anal 2016; 24:332-342. [PMID: 28911587 PMCID: PMC9339567 DOI: 10.1016/j.jfda.2015.11.010] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/07/2015] [Revised: 11/07/2015] [Accepted: 11/29/2015] [Indexed: 01/20/2023] Open
Abstract
A peptide from ostrich (Struthio camelus) egg white protein hydrolysate (OEWPH) was purified, characterized, and its antioxidant and enzyme inhibitory properties were evaluated. The OEWPH was prepared using pepsin and pancreatin, and then fractionated using reversed-phase high performance liquid chromatography. The antioxidant activity of the WG-9 peptide was investigated based on its scavenging capacity for 1,1-diphenyl-2-picrylhydrazyl (DPPH) radical, 2,20-azinobis (3-ethylbenzothiazoline-6-sulphonic acid) diammonium salt (ABTS), superoxide (O2•-), hydroxyl (OH•-), and lipid peroxidation inhibition. The angiotensin-converting enzyme (ACE) inhibitory activity and kinetic parameters of the peptide were determined using N-[3-(2-Furyl)acryloyl]-L-phenylalanyl-glycyl-glycine (FAPGG) as a substrate. Tandem mass spectrometry analysis of the purified peptide revealed a sequence of WESLSRLLG (MW: 1060 Da; WG-9). This peptide inhibited linoleic acid oxidation and acted as a DPPH (IC50 = 15 ± 0.4 μg/mL), ABTS (IC50 = 130 ± 4.5 μg/mL), superoxide (IC50 = 160 ± 6.4 μg/mL), and hydroxyl (IC50 = 150 ± 6.7 μg/mL) radical scavenger. The ACE-inhibitory activity and kinetic parameters of the WG-9 peptide were determined, showing an ACE inhibitory activity with IC50 of 46.7 ± 1.4 μg/mL. The parameters of peptide/ACE interactions were investigated by molecule docking. Furthermore, viability assays showed that the identified peptide had no cytotoxicity against an HFLF-PI-5 cell line. In conclusion, the WG-9 peptide showed potent antioxidant and ACE-inhibitory activity.
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Affiliation(s)
- Ahmad Asoodeh
- Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad,
Iran
| | - Masoud Homayouni-Tabrizi
- Department of Biochemistry and Biophysics, Mashhad Branch, Islamic Azad University, Mashhad,
Iran
| | - Hoda Shabestarian
- Department of Basic Science, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad,
Iran
| | - Shamsi Emtenani
- Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad,
Iran
| | - Shirin Emtenani
- Department of Chemistry, Faculty of Science, Ferdowsi University of Mashhad, Mashhad,
Iran
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Höglund K, Lequarré AS, Ljungvall I, Mc Entee K, Merveille AC, Wiberg M, Gouni V, Lundgren Willesen J, Hanås S, Wess G, Mejer Sørensen L, Tiret L, Kierczak M, Forsberg SKG, Seppälä E, Lindblad-Toh K, Lohi H, Chetboul V, Fredholm M, Häggström J. Effect of Breed on Plasma Endothelin-1 Concentration, Plasma Renin Activity, and Serum Cortisol Concentration in Healthy Dogs. J Vet Intern Med 2016; 30:566-73. [PMID: 26812988 PMCID: PMC4913606 DOI: 10.1111/jvim.13829] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2015] [Revised: 10/23/2015] [Accepted: 12/21/2015] [Indexed: 01/27/2023] Open
Abstract
BACKGROUND There are breed differences in several blood variables in healthy dogs. OBJECTIVE Investigate breed variation in plasma endothelin-1 (ET-1) concentration, plasma renin activity, and serum cortisol concentration. ANIMALS Five-hundred and thirty-one healthy dogs of 9 breeds examined at 5 centers (2-4 breeds/center). METHODS Prospective observational study. Circulating concentrations of ET-1 and cortisol, and renin activity, were measured using commercially available assays. Absence of organ-related or systemic disease was ensured by thorough clinical investigations, including blood pressure measurement, echocardiography, ECG, blood and urine analysis. RESULTS Median ET-1 concentration was 1.29 (interquartile range [IQR], 0.97-1.82) pg/mL, median cortisol concentration 46.0 (IQR, 29.0-80.8) nmol/L, and median renin activity 0.73 (IQR, 0.48-1.10) ng/mL/h in all dogs. Overall, breed differences were found in ET-1 and cortisol concentrations, and renin activity (P < .0001 for all). Pair-wise comparisons between breeds differed in 67% of comparisons for ET-1, 22% for cortisol, and 19% for renin activity, respectively. Within centers, breed differences were found at 5/5 centers for ET-1, 4/5 centers for cortisol, and 2/5 centers for renin activity. Newfoundlands had highest median ET-1 concentration, 3 times higher than Cavalier King Charles Spaniels, Doberman Pinschers, and Dachshunds. Median renin activity was highest in Dachshunds, twice the median value in Newfoundlands and Boxers. Median cortisol concentration was highest in Finnish Lapphunds, almost 3 times higher than in Boxers. CONCLUSIONS AND CLINICAL IMPORTANCE Breed variation might be important to take into consideration when interpreting test results in clinical studies.
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Affiliation(s)
- K Höglund
- Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - A-S Lequarré
- Faculty of Veterinary Medicine, University of Liège, Liège, Belgium
| | - I Ljungvall
- Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - K Mc Entee
- Faculty of Medicine, Université Libre de Bruxelles, Brussels, Belgium
| | - A-C Merveille
- Faculty of Veterinary Medicine, University of Liège, Liège, Belgium
| | - M Wiberg
- Faculty of Veterinary Medicine, University of Helsinki, Helsinki, Finland
| | - V Gouni
- Ecole nationale vétérinaire d'Alfort, Université Paris-Est Créteil, Créteil, France.,Inserm, U955, Equipe 3, Créteil, France
| | - J Lundgren Willesen
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - S Hanås
- Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Uppsala, Sweden.,Evidensia Animal Clinic, Västerås, Sweden
| | - G Wess
- Ludwig-Maximilians-Universität, Munich, Germany
| | - L Mejer Sørensen
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - L Tiret
- Ecole nationale vétérinaire d'Alfort, Université Paris-Est Créteil, Créteil, France.,Inserm, U955 IMRB, Equipe 10 BNMS, Créteil, France
| | - M Kierczak
- Faculty of Medicine, Uppsala University, Uppsala, Sweden
| | - S K G Forsberg
- Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Uppsala, Sweden
| | - E Seppälä
- University of Helsinki and Folkhälsan Research Center, Helsinki, Finland
| | - K Lindblad-Toh
- Faculty of Medicine, Uppsala University, Uppsala, Sweden.,Broad Institute of MIT and Harvard, Cambridge, MA
| | - H Lohi
- University of Helsinki and Folkhälsan Research Center, Helsinki, Finland
| | - V Chetboul
- Ecole nationale vétérinaire d'Alfort, Université Paris-Est Créteil, Créteil, France.,Inserm, U955, Equipe 3, Créteil, France
| | - M Fredholm
- Faculty of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark
| | - J Häggström
- Faculty of Veterinary Medicine and Animal Science, Swedish University of Agricultural Sciences, Uppsala, Sweden
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Holappa M, Vapaatalo H, Vaajanen A. Ocular renin-angiotensin system with special reference in the anterior part of the eye. World J Ophthalmol 2015; 5:110-124. [DOI: 10.5318/wjo.v5.i3.110] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/28/2015] [Revised: 03/21/2015] [Accepted: 06/16/2015] [Indexed: 02/06/2023] Open
Abstract
The renin-angiotensin system (RAS) regulates blood pressure (BP) homeostasis, systemic fluid volume and electrolyte balance. The RAS cascade includes over twenty peptidases, close to twenty angiotensin peptides and at least six receptors. Out of these, angiotensin II, angiotensin converting enzyme 1 and angiotensin II type 1 receptor (AngII-ACE1-AT1R) together with angiotensin (1-7), angiotensin converting enzyme 2 and Mas receptor (Ang(1-7)-ACE2-MasR) are regarded as the main components of RAS. In addition to circulating RAS, local RA-system exists in various organs. Local RA-systems are regarded as tissue-specific regulatory systems accounting for local effects and long term changes in different organs. Many of the central components such as the two main axes of RAS: AngII-ACE1-AT1R and Ang(1-7)-ACE2-MasR, have been identified in the human eye. Furthermore, it has been shown that systemic antihypertensive RAS- inhibiting medications lower intraocular pressure (IOP). These findings suggest the crucial role of RAS not only in the regulation of BP but also in the regulation of IOP, and RAS potentially plays a role in the development of glaucoma and antiglaucomatous drugs.
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Norcliffe-Kaufmann L, Katz SD, Axelrod F, Kaufmann H. Norepinephrine deficiency with normal blood pressure control in congenital insensitivity to pain with anhidrosis. Ann Neurol 2015; 77:743-52. [PMID: 25627679 PMCID: PMC5074379 DOI: 10.1002/ana.24377] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2014] [Revised: 12/30/2014] [Accepted: 01/19/2015] [Indexed: 12/13/2022]
Abstract
OBJECTIVE Congenital insensitivity to pain with anhidrosis (CIPA) is caused by mutations in the NKTR1 gene. This affects the development of nerve growth factor (NGF)-dependent neurons including sympathetic cholinergic neurons in the skin, causing anhidrosis. Cardiovascular and blood pressure regulation appears normal, but the integrity of sympathetic adrenergic neurons has not been tested. METHODS We examined the effect of posture on blood pressure, heart rate, plasma concentration of catecholamines, vasopressin, endothelin, and renin activity in 14 patients with CIPA, 10 patients with chronically deficient sympathetic activity (pure autonomic failure), and 15 normal age-matched controls. RESULTS In all 14 patients with CIPA, plasma norepinephrine levels were very low or undetectable and failed to increase when the patient was upright, yet upright blood pressure was well maintained. Plasma epinephrine levels were normal and increased when the patient was upright. Plasma renin activity also increased appropriately when the patient was upright and after furosemide-induced volume depletion. Nitric oxide-mediated endothelial function was intact. Patients with pure autonomic failure also had very low levels of plasma norepinephrine both supine and upright, but in contrast to patients with CIPA failed to maintain blood pressure upright. INTERPRETATION The results indicate that postganglionic sympathetic neurons are severely depleted in CIPA, but chromaffin cells of the adrenal medulla are spared. This confirms the differential effect of NGF signaling for sympathetic neural and chromaffin cell development. The finding that patients with CIPA maintain blood pressure well on standing challenges current concepts of the role of norepinephrine in the regulation of arterial pressure.
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Affiliation(s)
| | - Stuart D. Katz
- Department of Medicine, Division of Cardiology, New York University, USA
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Zhao Q, Huang H, Wang X, Wang X, Dai Z, Wan P, Guo Z, Yu S, Tang Y, Huang C. Changes of serum neurohormone after renal sympathetic denervation in dogs with pacing-induced heart failure. Int J Clin Exp Med 2014; 7:4024-4030. [PMID: 25550911 PMCID: PMC4276169] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2014] [Accepted: 09/20/2014] [Indexed: 06/04/2023]
Abstract
BACKGROUND Neurohormonal activation is a commonly cited array of phenomena in the body's physiologic response to heart failure (HF). The aim of the present study was to determine the change law of serum neurohormones after renal sympathetic denervation (RSD) in dogs with pacing-induced HF. METHODS Twenty-eight beagles were randomly divided into control group, RSD group, HF group and HF + RSD group. The control group was implanted pacemakers without pacing; the RSD group underwent renal artery ablation without pacing; the HF group was implanted pacemakers with ventricular pacing at 240 bpm for 3 weeks; and HF + RSD group underwent renal artery ablation and with ventricular pacing at 240 bpm for 3 weeks. Blood samples were taken at baseline, and 3, 6, 9, 12, 15, 18, 21 days in all the dogs for neurohormones measurement. RESULTS After 3 weeks, the systolic femoral artery pressures in the HF and HF + RSD groups were reduced after pacing 3 weeks. There was an increase significantly in BNP, angiotensin II, aldosterone, endothelin-1 and decrease in renalase after 3 weeks when compared with baseline in HF group. RSD significantly suppressed the changes of plasma neurohormones concentration in experimental HF, but RSD had not obviously impact on the levels of plasma neurohormones during 3 weeks in RSD group. CONCLUSIONS RSD attenuates the changes of levels of plasma neurohormones in the activated renin-angiotensin-aldosterone system (RAAS) but had not obviously effect in the normal physiology of RAAS.
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Affiliation(s)
- Qingyan Zhao
- Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University 238 Jiefang Road, Wuhan City 430060, P. R. of China
| | - He Huang
- Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University 238 Jiefang Road, Wuhan City 430060, P. R. of China
| | - Xule Wang
- Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University 238 Jiefang Road, Wuhan City 430060, P. R. of China
| | - Xiaozhan Wang
- Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University 238 Jiefang Road, Wuhan City 430060, P. R. of China
| | - Zixuan Dai
- Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University 238 Jiefang Road, Wuhan City 430060, P. R. of China
| | - Peixing Wan
- Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University 238 Jiefang Road, Wuhan City 430060, P. R. of China
| | - Zongwen Guo
- Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University 238 Jiefang Road, Wuhan City 430060, P. R. of China
| | - Shengbo Yu
- Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University 238 Jiefang Road, Wuhan City 430060, P. R. of China
| | - Yanhong Tang
- Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University 238 Jiefang Road, Wuhan City 430060, P. R. of China
| | - Congxin Huang
- Cardiovascular Research Institute of Wuhan University, Renmin Hospital of Wuhan University 238 Jiefang Road, Wuhan City 430060, P. R. of China
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Thomas CM, Yong QC, Rosa RM, Seqqat R, Gopal S, Casarini DE, Jones WK, Gupta S, Baker KM, Kumar R. Cardiac-specific suppression of NF-κB signaling prevents diabetic cardiomyopathy via inhibition of the renin-angiotensin system. Am J Physiol Heart Circ Physiol 2014; 307:H1036-45. [PMID: 25085967 DOI: 10.1152/ajpheart.00340.2014] [Citation(s) in RCA: 52] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Activation of NF-κB signaling in the heart may be protective or deleterious depending on the pathological context. In diabetes, the role of NF-κB in cardiac dysfunction has been investigated using pharmacological approaches that have a limitation of being nonspecific. Furthermore, the specific cellular pathways by which NF-κB modulates heart function in diabetes have not been identified. To address these questions, we used a transgenic mouse line expressing mutated IκB-α in the heart (3M mice), which prevented activation of canonical NF-κB signaling. Diabetes was developed by streptozotocin injections in wild-type (WT) and 3M mice. Diabetic WT mice developed systolic and diastolic cardiac dysfunction by the 12th week, as measured by echocardiography. In contrast, cardiac function was preserved in 3M mice up to 24 wk of diabetes. Diabetes induced an elevation in cardiac oxidative stress in diabetic WT mice but not 3M mice compared with nondiabetic control mice. In diabetic WT mice, an increase in the phospholamban/sarco(endo)plasmic reticulum Ca(2+)-ATPase 2 ratio and decrease in ryanodine receptor expression were observed, whereas diabetic 3M mice showed an opposite effect on these parameters of Ca(2+) handling. Significantly, renin-angiotensin system activity was suppressed in diabetic 3M mice compared with an increase in WT animals. In conclusion, these results demonstrate that inhibition of NF-κB signaling in the heart prevents diabetes-induced cardiac dysfunction through preserved Ca(2+) handling and inhibition of the cardiac renin-angiotensin system.
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Affiliation(s)
- Candice M Thomas
- Division of Molecular Cardiology, Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Baylor Scott & White Health, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas
| | - Qian Chen Yong
- Division of Molecular Cardiology, Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Baylor Scott & White Health, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas
| | - Rodolfo M Rosa
- Nephrology Division, Department of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil; and
| | - Rachid Seqqat
- Division of Molecular Cardiology, Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Baylor Scott & White Health, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas
| | - Shanthi Gopal
- Central Texas Veterans Health Care System, Temple, Texas
| | - Dulce E Casarini
- Nephrology Division, Department of Medicine, Federal University of Sao Paulo, Sao Paulo, Brazil; and
| | - W Keith Jones
- Molecular Pharmacology and Therapeutics, Loyola University Chicago, Maywood, Illinois
| | - Sudhiranjan Gupta
- Division of Molecular Cardiology, Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Baylor Scott & White Health, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas
| | - Kenneth M Baker
- Division of Molecular Cardiology, Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Baylor Scott & White Health, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas
| | - Rajesh Kumar
- Division of Molecular Cardiology, Department of Medicine, Texas A&M Health Science Center, College of Medicine, Temple, Texas; Baylor Scott & White Health, Temple, Texas; Central Texas Veterans Health Care System, Temple, Texas;
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