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El Mouhayyar C, Chhikara M, Tang M, Nigwekar SU. Clinical implications of mineralocorticoid receptor overactivation. Clin Kidney J 2025; 18:sfae346. [PMID: 39781481 PMCID: PMC11704795 DOI: 10.1093/ckj/sfae346] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/29/2024] [Indexed: 01/12/2025] Open
Abstract
The mineralocorticoid receptor (MR) is a nuclear transcription factor that plays a critical role in regulating fluid, electrolytes, blood pressure, and hemodynamic stability. In conditions such as chronic kidney disease (CKD) and heart failure (HF), MR overactivation leads to increased salt and water retention, inflammatory and fibrotic gene expression, and organ injury. The MR is essential for transcriptional regulation and is implicated in metabolic, proinflammatory, and pro-fibrotic pathways. It is widely expressed in various cell types throughout the body, including the gastrointestinal tract, heart, brain, kidneys, immune cells, and vasculature. Animal studies suggest that MR activation induces oxidative stress in the kidneys and mediates renal inflammation and fibrosis. Immune cell-specific deletion of MR has shown protection against cardiac fibrosis, indicating the MR's role in pathological remodeling. In vascular smooth muscle cells, the MR regulates vascular tone and vasoconstriction. Mineralocorticoid receptor antagonists (MRAs) can be categorized based on their chemical structure as either steroidal or nonsteroidal. Steroidal MRAs (sMRA), such as spironolactone and eplerenone, have demonstrated cardiovascular benefits but are limited by hyperkalemia, gynecomastia, and sexual dysfunction. Nonsteroidal MRAs (nsMRA) have shown promise in preclinical studies and clinical trials. They offer a promising alternative by effectively blocking MR without hormone-like effects, potentially improving cardiovascular and renal disease management. Further education is necessary regarding the significance of MRA utilization in CKD and HF, balancing benefits with the risk of hyperkalemia. This risk could be mitigated by combining MRAs with potassium-binding agents. Studies are underway to explore the synergistic effects between nsMRAs and other agents, such as SGLT-2i inhibitors and Glucagon-like peptide-1 agonists, to optimize cardiorenal outcomes. Overall, MR overactivation remains a significant therapeutic target, with nsMRAs showing promise as pivotal therapies in CKD and HF management. This review highlights the evolving landscape of MR-targeted therapies, their molecular mechanisms, and clinical implications in cardiorenal diseases.
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Affiliation(s)
- Christopher El Mouhayyar
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | | | - Mengyao Tang
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
| | - Sagar U Nigwekar
- Division of Nephrology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA
- Harvard Medical School, Boston, MA, USA
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Arendshorst WJ, Vendrov AE, Kumar N, Ganesh SK, Madamanchi NR. Oxidative Stress in Kidney Injury and Hypertension. Antioxidants (Basel) 2024; 13:1454. [PMID: 39765782 PMCID: PMC11672783 DOI: 10.3390/antiox13121454] [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: 09/27/2024] [Revised: 11/09/2024] [Accepted: 11/18/2024] [Indexed: 01/11/2025] Open
Abstract
Hypertension (HTN) is a major contributor to kidney damage, leading to conditions such as nephrosclerosis and hypertensive nephropathy, significant causes of chronic kidney disease (CKD) and end-stage renal disease (ESRD). HTN is also a risk factor for stroke and coronary heart disease. Oxidative stress, inflammation, and activation of the renin-angiotensin-aldosterone system (RAAS) play critical roles in causing kidney injury in HTN. Genetic and environmental factors influence the susceptibility to hypertensive renal damage, with African American populations having a higher tendency due to genetic variants. Managing blood pressure (BP) effectively with treatments targeting RAAS activation, oxidative stress, and inflammation is crucial in preventing renal damage and the progression of HTN-related CKD and ESRD. Interactions between genetic and environmental factors impacting kidney function abnormalities are central to HTN development. Animal studies indicate that genetic factors significantly influence BP regulation. Anti-natriuretic mechanisms can reset the pressure-natriuresis relationship, requiring a higher BP to excrete sodium matched to intake. Activation of intrarenal angiotensin II receptors contributes to sodium retention and high BP. In HTN, the gut microbiome can affect BP by influencing energy metabolism and inflammatory pathways. Animal models, such as the spontaneously hypertensive rat and the chronic angiotensin II infusion model, mirror human essential hypertension and highlight the significance of the kidney in HTN pathogenesis. Overproduction of reactive oxygen species (ROS) plays a crucial role in the development and progression of HTN, impacting renal function and BP regulation. Targeting specific NADPH oxidase (NOX) isoforms to inhibit ROS production and enhance antioxidant mechanisms may improve renal structure and function while lowering blood pressure. Therapies like SGLT2 inhibitors and mineralocorticoid receptor antagonists have shown promise in reducing oxidative stress, inflammation, and RAAS activity, offering renal and antihypertensive protection in managing HTN and CKD. This review emphasizes the critical role of NOX in the development and progression of HTN, focusing on its impact on renal function and BP regulation. Effective BP management and targeting oxidative stress, inflammation, and RAAS activation, is crucial in preventing renal damage and the progression of HTN-related CKD and ESRD.
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Affiliation(s)
- Willaim J. Arendshorst
- Department of Cell Biology and Physiology, University of North Carolina, Chapel Hill, NC 27599, USA;
| | - Aleksandr E. Vendrov
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (A.E.V.); (N.K.); (S.K.G.)
| | - Nitin Kumar
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (A.E.V.); (N.K.); (S.K.G.)
- Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Santhi K. Ganesh
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (A.E.V.); (N.K.); (S.K.G.)
- Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Nageswara R. Madamanchi
- Department of Internal Medicine, Division of Cardiovascular Medicine, University of Michigan, Ann Arbor, MI 48109, USA; (A.E.V.); (N.K.); (S.K.G.)
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Janota O, Kwiendacz H, Olejarz A, Włosowicz A, Pabis P, Gumprecht J, Alam U, Lip GYH, Nabrdalik K. Cardio-reno-vascular protection in type 2 diabetes mellitus: new insights into pharmacotherapeutic management. Expert Opin Pharmacother 2024; 25:1605-1624. [PMID: 39150280 DOI: 10.1080/14656566.2024.2392017] [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: 06/13/2024] [Revised: 08/03/2024] [Accepted: 08/09/2024] [Indexed: 08/17/2024]
Abstract
INTRODUCTION From 2008 and following the withdrawal of rosiglitazone, obligatory cardiovascular outcomes trials are performed for glucose lowering drugs introduced to the market to ensure their cardiovascular (CV) safety. Paradoxically, these studies have demonstrated CV safety but also shown additional cardio-reno-vascular protection of some therapeutic agents. Additionally, nonsteroidal mineralocorticoid receptor antagonists (ns-MRA) have emerged as novel drugs for cardio - and renoprotection in type 2 diabetes (T2D) and chronic kidney disease (CKD). In addition to atherosclerotic CV disease, heart failure (HF) and CKD are important clinical problems in T2D leading to poor quality of life and premature death as such cardio-reno-vascular protection is an important clinical issue. AREAS COVERED We provide new insights into pharmacotherapeutic cardio-reno-vascular protection in T2D based on the new glucose lowering drugs and ns-MRA. PUB MED/CINAHL/Web of Science/Scopus were searched (May 2024). EXPERT OPINION The conventional glucose lowering approach alone which was implemented for decades is now replaced by the use of disease modifying drugs which lower the rates of CV events, HF decompensation, hospitalization due to HF, slow progression of CKD and all-cause mortality. Indeed, the choice of medications in T2D should be focused on underlying co-morbidities with cardio-reno-vascular protection rather than a gluco-centric approach.
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Affiliation(s)
- Oliwia Janota
- Doctoral School, Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
- Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Hanna Kwiendacz
- Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Anna Olejarz
- Students' Scientific Association by the Department of Internal Medicine, Diabetology and Nephrology in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Aleksandra Włosowicz
- Students' Scientific Association by the Department of Internal Medicine, Diabetology and Nephrology in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Patrycja Pabis
- Students' Scientific Association by the Department of Internal Medicine, Diabetology and Nephrology in Zabrze, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Janusz Gumprecht
- Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
| | - Uazman Alam
- Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK
- Diabetes & Endocrinology Research and Pain Research Institute, Institute of Life Course and Medical Sciences, University of Liverpool and Liverpool University Hospital NHS Foundation Trust, Liverpool, UK
| | - Gregory Y H Lip
- Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK
- Department of Clinical Medicine, Aalborg University, Aalborg, Denmark
| | - Katarzyna Nabrdalik
- Department of Internal Medicine, Diabetology and Nephrology, Faculty of Medical Sciences in Zabrze, Medical University of Silesia, Katowice, Poland
- Liverpool Centre for Cardiovascular Science at University of Liverpool, Liverpool John Moores University and Liverpool Heart & Chest Hospital, Liverpool, UK
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Ávila-Martínez DV, Mixtega-Ruiz WK, Hurtado-Capetillo JM, Lopez-Franco O, Flores-Muñoz M. Counter-regulatory RAS peptides: new therapy targets for inflammation and fibrotic diseases? Front Pharmacol 2024; 15:1377113. [PMID: 38666016 PMCID: PMC11044688 DOI: 10.3389/fphar.2024.1377113] [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: 01/26/2024] [Accepted: 03/18/2024] [Indexed: 04/28/2024] Open
Abstract
The renin-angiotensin system (RAS) is an important cascade of enzymes and peptides that regulates blood pressure, volume, and electrolytes. Within this complex system of reactions, its counter-regulatory axis has attracted attention, which has been associated with the pathophysiology of inflammatory and fibrotic diseases. This review article analyzes the impact of different components of the counter-regulatory axis of the RAS on different pathologies. Of these peptides, Angiotensin-(1-7), angiotensin-(1-9) and alamandine have been evaluated in a wide variety of in vitro and in vivo studies, where not only they counteract the actions of the classical axis, but also exhibit independent anti-inflammatory and fibrotic actions when binding to specific receptors, mainly in heart, kidney, and lung. Other functional peptides are also addressed, which despite no reports associated with inflammation and fibrosis to date were found, they could represent a potential target of study. Furthermore, the association of agonists of the counter-regulatory axis is analyzed, highlighting their contribution to the modulation of the inflammatory response counteracting the development of fibrotic events. This article shows an overview of the importance of the RAS in the resolution of inflammatory and fibrotic diseases, offering an understanding of the individual components as potential treatments.
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Affiliation(s)
- Diana V Ávila-Martínez
- Laboratorio de Medicina Traslacional, Instituto de Ciencias de la Salud, Universidad Veracruzana, Xalapa, Mexico
- Doctorado en Ciencias de la Salud, Instituto de Ciencias de la Salud, Universidad Veracruzana, Xalapa, Mexico
| | - Wendy K Mixtega-Ruiz
- Laboratorio de Medicina Traslacional, Instituto de Ciencias de la Salud, Universidad Veracruzana, Xalapa, Mexico
- Doctorado en Ciencias Biológicas, Centro Tlaxcala de Biología de la Conducta, Universidad Autónoma de Tlaxcala, Tlaxcala, Mexico
| | | | - Oscar Lopez-Franco
- Laboratorio de Medicina Traslacional, Instituto de Ciencias de la Salud, Universidad Veracruzana, Xalapa, Mexico
- Doctorado en Ciencias de la Salud, Instituto de Ciencias de la Salud, Universidad Veracruzana, Xalapa, Mexico
| | - Mónica Flores-Muñoz
- Laboratorio de Medicina Traslacional, Instituto de Ciencias de la Salud, Universidad Veracruzana, Xalapa, Mexico
- Doctorado en Ciencias de la Salud, Instituto de Ciencias de la Salud, Universidad Veracruzana, Xalapa, Mexico
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Wegner E, Mickan T, Truffel S, Slotina E, Müller L, Wunderlich F, Harper A, Ritz U, Rommens PM, Gercek E, Drees P, Baranowski A. The effect of losartan on the development of post-traumatic joint stiffness in a rat model. Biomed Pharmacother 2023; 166:115291. [PMID: 37557010 DOI: 10.1016/j.biopha.2023.115291] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/08/2023] [Revised: 07/27/2023] [Accepted: 08/04/2023] [Indexed: 08/11/2023] Open
Abstract
Post-traumatic joint stiffness (PTJS) is accompanied by a multidimensional disturbance of joint architecture. Pharmacological approaches represent promising alternatives as the traumatic nature of current therapeutic standards may lead to PTJS' progression. Losartan is an auspicious candidate, as it has demonstrated an antifibrotic effect in other organs. Forty-eight Sprague Dawley rats were randomized into equally sized losartan or control groups. After a standardized knee trauma, the joint was immobilized for either 2 weeks (n = 16), 4 weeks (n = 16) or 4 weeks with re-mobilization for an additional 4 weeks (n = 16). Pharmacotherapy with losartan or placebo (30 mg/kg/day) was initiated on the day of trauma and continued for the entire course. Joint contracture was measured alongside histological and molecular biological assessments. There were no significant biomechanical changes in joint contracture over time, comparing short-term (2 weeks) with long-term losartan therapy (4 weeks). However, comparing the formation of PTJS with that of the control, there was a trend toward improvement of joint mobility of 10.5° (p 0.09) under the influence of losartan. During the re-mobilization phase, no significant effect of losartan on range of motion (ROM) was demonstrated. At a cellular level, losartan significantly reduced myofibroblast counts by up to 72 % (4 weeks, p ≤ 0.001) without effecting the capsular configuration. Differences in expression levels of profibrotic factors (TGF-β, CTGF, Il-6) were most pronounced at week 4. The antifibrotic properties of losartan are not prominent enough to completely prevent the development of PTJS after severe joint injury.
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Affiliation(s)
- Erik Wegner
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Tim Mickan
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Sebastian Truffel
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Ekaterina Slotina
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Lukas Müller
- Department of Diagnostic and Interventional Radiology, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany; Mainz Research School of Translational Biomedicine, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Felix Wunderlich
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Austin Harper
- St. George's University School of Medicine, True Blue, St. George, Grenada
| | - Ulrike Ritz
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Pol M Rommens
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Erol Gercek
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Philipp Drees
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany
| | - Andreas Baranowski
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Center of the Johannes Gutenberg University, Mainz 55131, Germany.
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Gaggar P, Raju DSB, Tej MR, Pragna P. Late-Onset Bartter's Syndrome Type II with End-Stage Renal Disease Due to a Novel Mutation in KCNJ1 Gene in an Indian Adult Male - A Case Report. Indian J Nephrol 2023; 33:57-60. [PMID: 37197039 PMCID: PMC10185019 DOI: 10.4103/ijn.ijn_383_21] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/07/2021] [Accepted: 10/06/2021] [Indexed: 11/04/2022] Open
Abstract
Mutations in ROMK1 potassium channel gene (KCNJ1) causes antenatal/neonatal Bartter's syndrome type II, which presents with renal salt wasting, hypokalemic metabolic alkalosis, secondary hyperaldosteronism, hypercalciuria, and nephrocalcinosis. We herein describe a case of late-onset Bartter's syndrome type II with progressive renal failure requiring renal replacement therapy secondary to a novel homozygous missense mutation in Exon 2 of KCNJ1 gene (c.500G>A). With this case, we aim to highlight the need for a high index of suspicion and the role of genetic evaluation to diagnose clinically unclassified cases of nephrocalcinosis with renal electrolyte abnormalities more so in late and atypical presentations.
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Affiliation(s)
- Payal Gaggar
- Department of Nephrology, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana, India
| | - D Sree Bhushan Raju
- Department of Nephrology, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana, India
| | - M Ravi Tej
- Department of Nephrology, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana, India
| | - P Pragna
- Department of Nephrology, Nizam’s Institute of Medical Sciences, Punjagutta, Hyderabad, Telangana, India
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Qiang P, Hao J, Yang F, Han Y, Chang Y, Xian Y, Xiong Y, Gao X, Liang L, Shimosawa T, Xu Q. Esaxerenone inhibits the macrophage-to-myofibroblast transition through mineralocorticoid receptor/TGF-β1 pathway in mice induced with aldosterone. Front Immunol 2022; 13:948658. [PMID: 36148244 PMCID: PMC9485811 DOI: 10.3389/fimmu.2022.948658] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/20/2022] [Accepted: 08/16/2022] [Indexed: 11/17/2022] Open
Abstract
Renal fibrosis is the inevitable pathway of the progression of chronic kidney disease to end-stage renal disease, which manifests as progressive glomerulosclerosis and renal interstitial fibrosis. In a previous study, we observed severe interstitial fibrosis in the contralateral kidneys of 6-month unilateral ureteral obstruction (UUO) rats, which was accompanied by increased macrophage infiltration and phenotypic transformation; after eplerenone administration, these effects were reduced. Therefore, we hypothesized that this effect was closely related to mineralocorticoid receptor (MR) activation induced by the increased aldosterone (ALD) level. In this study, we used uninephrectomy plus continuous aldosterone infusion in mice to observe whether aldosterone induced macrophage-to-myofibroblast transition (MMT) and renal fibrosis and investigated the signaling pathways. Notably, aldosterone induced predominantly M1 macrophage-to-myofibroblast transition by activating MR and upregulating TGF-β1 expression, which promoted renal fibrosis. These effects were antagonized by the MR blocker esaxerenone. These findings suggest that targeting the MR/TGF-β1 pathway may be an effective therapeutic strategy for renal fibrosis.
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Affiliation(s)
- Panpan Qiang
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Juan Hao
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Fan Yang
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, China
- Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Yutong Han
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Yi Chang
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, China
- Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Yunqian Xian
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Yunzhao Xiong
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, China
- Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Xiaomeng Gao
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, China
| | - Lijuan Liang
- Department of Clinical Laboratory, School of Medicine, International University of Health and Welfare, Narita, Japan
| | - Tatsuo Shimosawa
- Department of Clinical Laboratory, School of Medicine, International University of Health and Welfare, Narita, Japan
- *Correspondence: Qingyou Xu, ; Tatsuo Shimosawa,
| | - Qingyou Xu
- Graduate School, Hebei University of Chinese Medicine, Shijiazhuang, China
- Hebei Key Laboratory of Integrative Medicine on Liver-Kidney Patterns, Hebei University of Chinese Medicine, Shijiazhuang, China
- Institute of Integrative Medicine, College of Integrative Medicine, Hebei University of Chinese Medicine, Shijiazhuang, China
- *Correspondence: Qingyou Xu, ; Tatsuo Shimosawa,
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DeFronzo RA, Bakris GL. Modifying chronic kidney disease progression with the mineralocorticoid receptor antagonist finerenone in patients with type 2 diabetes. Diabetes Obes Metab 2022; 24:1197-1205. [PMID: 35302284 PMCID: PMC9323420 DOI: 10.1111/dom.14696] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2022] [Revised: 03/07/2022] [Accepted: 03/16/2022] [Indexed: 11/29/2022]
Abstract
In patients with type 2 diabetes, chronic kidney disease (CKD) is the most common cause of kidney failure. With its increasing prevalence and limited treatment options, CKD is a major contributor to the global burden of disease. Although recent guidelines for the control of hypertension and hyperglycaemia, as well as the use of renin-angiotensin system inhibitors and, more recently, sodium-glucose co-transporter-2 inhibitors, have improved outcomes for patients with CKD and diabetes, there is still a high residual risk of CKD progression and adverse cardiovascular events. In this review, we discuss the recently published FIDELIO-DKD and FIGARO-DKD studies and FIDELITY prespecified individual patient analysis. Together, these studies have established finerenone, a novel non-steroidal mineralocorticoid receptor antagonist, as an effective treatment for kidney and cardiovascular protection and welcome addition to the pillars of treatment to slow CKD progression in patients with type 2 diabetes.
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Affiliation(s)
- Ralph A. DeFronzo
- Diabetes Division, Dept of Medicine, UT Health and Texas Diabetes InstituteSan AntonioTexasUSA
| | - George L. Bakris
- University of Chicago School of Medicine, Dept of MedicineChicagoIllinoisUSA
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The non-steroidal mineralocorticoid receptor antagonist finerenone is a novel therapeutic option for patients with Type 2 diabetes and chronic kidney disease. Clin Sci (Lond) 2022; 136:1005-1017. [PMID: 35765983 DOI: 10.1042/cs20220212] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/28/2022] [Revised: 06/01/2022] [Accepted: 06/16/2022] [Indexed: 11/17/2022]
Abstract
Despite strong preclinical data supporting the use of mineralocorticoid receptor antagonists (MRAs) to provide cardiorenal protection in rodent models of diabetes, the clinical evidence of their utility in treating chronic kidney disease (CKD) has been limited. Two major clinical trials (FIDELIO-DKD and FIGARO-DKD) including more than 13,000 patients with albuminuric CKD and Type 2 diabetes randomized to placebo or finerenone (MRA) have recently provided exciting results showing a significant risk reduction for kidney and cardiovascular outcomes. In this review, we will summarize the major findings of these trials, together with post-hoc and pooled analyses that have allowed evaluation of the efficacy and safety of finerenone across the spectrum of CKD, revealing significant protective effects of finerenone against kidney failure, new-onset atrial fibrillation or flutter, new-onset heart failure, cardiovascular death, and first and total heart-failure hospitalizations. Moreover, we will discuss the current evidence that supports the combined use of MRAs with sodium-glucose co-transporter-2 inhibitors, either by providing an additive cardiorenal benefit or by decreasing the risk of hyperkalemia. Although the mechanisms of protection by finerenone have only been partially explored in patients, rodent studies have shed light on its anti-inflammatory and anti-fibrotic effects in models of kidney disease, which is one of the main drivers for testing the efficacy of finerenone in non-diabetic CKD patients in the ongoing FIND-CKD trial.
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Lin X, Ullah MHE, Wu X, Xu F, Shan SK, Lei LM, Yuan LQ, Liu J. Cerebro-Cardiovascular Risk, Target Organ Damage, and Treatment Outcomes in Primary Aldosteronism. Front Cardiovasc Med 2022; 8:798364. [PMID: 35187110 PMCID: PMC8847442 DOI: 10.3389/fcvm.2021.798364] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 12/20/2021] [Indexed: 02/03/2023] Open
Abstract
Primary aldosteronism (PA) is the most common type of endocrine hypertension, and numerous experimental and clinical evidence have verified that prolonged exposure to excess aldosterone is responsible for an increased risk of cerebro-cardiovascular events and target organ damage (TOD) in patients with PA. Therefore, focusing on restoring the toxic effects of excess aldosterone on the target organs is very important to reduce cerebro-cardiovascular events. Current evidence convincingly demonstrates that both surgical and medical treatment strategies would benefit cerebro-cardiovascular outcomes and mortality in the long term. Understanding cerebro-cardiovascular risk in PA would help clinical doctors to achieve both early diagnosis and treatment. Therefore, in this review, we will summarize the cerebro-cardiovascular risk in PA, focusing on the TOD of aldosterone, including brain, heart, vascular system, renal, adipose tissues, diabetes, and obstructive sleep apnea (OSA). Furthermore, the various treatment outcomes of adrenalectomy and medical treatment for patients with PA will also be discussed. We hope this knowledge will help improve cerebro-cardiovascular prognosis and reduce the incidence and mortality of cerebro-cardiovascular events in patients with PA.
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Affiliation(s)
- Xiao Lin
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Muhammad Hasnain Ehsan Ullah
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Xiong Wu
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Feng Xu
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Su-Kang Shan
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Li-Min Lei
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
| | - Ling-Qing Yuan
- Department of Endocrinology and Metabolism, National Clinical Research Center for Metabolic Diseases, The Second Xiangya Hospital, Central South University, Changsha, China
- Ling-Qing Yuan
| | - Jun Liu
- Department of Radiology, The Second Xiangya Hospital, Central South University, Changsha, China
- Clinical Research Center for Medical Imaging in Hunan Province, Changsha, China
- Department of Radiology Quality Control Center in Hunan Province, Changsha, China
- *Correspondence: Jun Liu
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11
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Shenoy SV, Nagaraju SP, Bhojaraja MV, Prabhu RA, Rangaswamy D, Rao IR. Sodium-glucose cotransporter-2 inhibitors and non-steroidal mineralocorticoid receptor antagonists: Ushering in a new era of nephroprotection beyond renin-angiotensin system blockade. Nephrology (Carlton) 2021; 26:858-871. [PMID: 34176194 DOI: 10.1111/nep.13917] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 06/13/2021] [Accepted: 06/20/2021] [Indexed: 12/28/2022]
Abstract
The therapeutic options for preventing or slowing the progression of chronic kidney disease (CKD) have been thus far limited. While angiotensin converting enzyme inhibitors (ACEi) and angiotensin receptor blockers (ARBs) are, without a doubt, safe and effective drugs, a significant proportion of patients with CKD still progress to end-stage kidney disease. After decades of negative trials, nephrologists have finally found cause for optimism with the introduction of sodium-glucose cotransporter-2 (SGLT2) inhibitors and non-steroidal mineralocorticoid receptor antagonists (MRAs). Recent trials such as EMPA-REG OUTCOME and CREDENCE have provided evidence of the renal benefits of SGLT2 inhibitors, which have now found widespread acceptance as first-line agents for diabetic CKD, in addition to ACEi/ARBs. Considering results from the DAPA-CKD study, it is expected that their use will soon be expanded to other causes of albuminuric CKD as well, although confirmation from further trials, such as the EMPA-KIDNEY study is awaited. Likewise, although the role of mineralocorticoid receptor overactivation in CKD progression has been known for decades, it is only now with the FIDELIO-DKD study that we have evidence of benefits of MRAs on hard renal endpoints, specifically in patients with diabetic CKD. While further research is ongoing, given the evidence of synergism between the three drug classes, it is foreseeable that a combination of two or more of these drugs may soon become the standard of care for CKD, regardless of underlying aetiology. This review describes pathophysiologic mechanisms, current evidence and future perspectives on the use of SGLT2 inhibitors and novel MRAs in CKD.
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Affiliation(s)
- Srinivas Vinayak Shenoy
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Shankar Prasad Nagaraju
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | | | - Ravindra Attur Prabhu
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Dharshan Rangaswamy
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
| | - Indu Ramachandra Rao
- Department of Nephrology, Kasturba Medical College, Manipal, Manipal Academy of Higher Education, Manipal, Karnataka, India
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12
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He YL, Wen JG, Pu QS, Wen YB, Zhai RQ, Chen Y, Ma Y, Liu EP, Xing D, Ji FP, Yang XH, Wang QW, Wang Y, Bauer SB. Losartan prevents bladder fibrosis and protects renal function in rat with neurogenic paralysis bladder. Neurourol Urodyn 2021; 40:137-146. [PMID: 33606304 DOI: 10.1002/nau.24567] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Revised: 10/17/2020] [Accepted: 10/26/2020] [Indexed: 12/14/2022]
Abstract
AIMS To investigate the effect of losartan on preventing bladder fibrosis and protecting renal function in rats with neurogenic paralysis bladder (NPB). MATERIALS AND METHODS Rats were assigned to the transecting spinal nerves group (TSNG), transecting spinal nerves + losartan group (LSTG), and control group (CG). On Day 32 postsurgery, bladder capacity (BC), bladder compliance (ΔC), bladder leakage pressure (Pves.leak ) of TSNG and LSTG while BC, ΔC, and bladder threshold pressure (Pves.thre ) of CG were measured by cystometry in each cohort. Renal function and the expression quantity of Angiotensin Ⅱ (Ang II) in blood were detected, in addition Ang II, Ang II Type 1 receptor (AT1), transformation growth factor β1 (TGFβ1), Collagen Ⅲ, and collagen fibrin in the bladder tissue were detected too. RESULTS ΔC in TSNG and LSTG decreased significantly compared to the CG. Pves.leak in TSNG and LSTG were significantly higher than Pves.thre in CG. Renal function of both TSNG and LSTG decreased significantly compared with the CG, but renal function in LSTG was better than in TSNG. Ang Ⅱ in blood and bladder tissue in TSNG and LSTG increased significantly compared with CG. AT1 was expressed in the bladder tissue of all rats. The TGFβ1, Collagen Ⅲ, and collagen fibrin expression level increased significantly in TSNG compared with LSTG and CG, while these levels were not significantly different between CG and LSTG. CONCLUSION Losartan might prevent NPB fibrosis by stopping the upregulated signaling of Ang II/AT1/TGFβ1 and consequently may reduce kidney damage from occurring.
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Affiliation(s)
- Yu L He
- Pediatric Urodynamic Centre, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Joint International Pediatric Urodynamic Laboratory, Zhengzhou, China.,Pediatric surgery, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Jian G Wen
- Pediatric Urodynamic Centre, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Joint International Pediatric Urodynamic Laboratory, Zhengzhou, China
| | - Qing S Pu
- Pediatric Urodynamic Centre, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Joint International Pediatric Urodynamic Laboratory, Zhengzhou, China
| | - Yi B Wen
- Pediatric Urodynamic Centre, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Joint International Pediatric Urodynamic Laboratory, Zhengzhou, China
| | - Rong Q Zhai
- Pediatric Urodynamic Centre, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Joint International Pediatric Urodynamic Laboratory, Zhengzhou, China
| | - Yan Chen
- Pediatric Urodynamic Centre, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Joint International Pediatric Urodynamic Laboratory, Zhengzhou, China
| | - Yuan Ma
- Pediatric Urodynamic Centre, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Joint International Pediatric Urodynamic Laboratory, Zhengzhou, China
| | - Er P Liu
- Pediatric Urodynamic Centre, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Joint International Pediatric Urodynamic Laboratory, Zhengzhou, China
| | - Dong Xing
- Pediatric Urodynamic Centre, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Joint International Pediatric Urodynamic Laboratory, Zhengzhou, China
| | - Feng P Ji
- Pediatric Urodynamic Centre, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Joint International Pediatric Urodynamic Laboratory, Zhengzhou, China
| | - Xing H Yang
- Pediatric Urodynamic Centre, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Henan Joint International Pediatric Urodynamic Laboratory, Zhengzhou, China
| | - Qing W Wang
- Pediatric Urodynamic Centre, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Yan Wang
- Pediatric Urodynamic Centre, First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Stuart B Bauer
- Department of Urology, Boston Children's Hospital, Boston, Massachusetts, USA
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13
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Abstract
Significance: Fibrosis is a stereotypic, multicellular tissue response to diverse types of injuries that fundamentally result from a failure of cell/tissue regeneration. This complex tissue remodeling response disrupts cellular/matrix composition and homeostatic cell-cell interactions, leading to loss of normal tissue architecture and progressive loss of organ structure/function. Fibrosis is a common feature of chronic diseases that may affect the lung, kidney, liver, and heart. Recent Advances: There is emerging evidence to support a combination of genetic, environmental, and age-related risk factors contributing to susceptibility and/or progression of fibrosis in different organ systems. A core pathway in fibrogenesis involving these organs is the induction and activation of nicotinamide adenine dinucleotide phosphate oxidase (NOX) family enzymes. Critical Issues: We explore current pharmaceutical approaches to targeting NOX enzymes, including repurposing of currently U.S. Food and Drug Administration (FDA)-approved drugs. Specific inhibitors of various NOX homologs will aid establishing roles of NOXs in the various organ fibroses and potential efficacy to impede/halt disease progression. Future Directions: The discovery of novel and highly specific NOX inhibitors will provide opportunities to develop NOX inhibitors for treatment of fibrotic pathologies.
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Affiliation(s)
- Karen Bernard
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
| | - Victor J Thannickal
- Division of Pulmonary, Allergy, and Critical Care Medicine, Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA
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14
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Spencer S, Wheeler‐Jones C, Elliott J. Aldosterone and the mineralocorticoid receptor in renal injury: A potential therapeutic target in feline chronic kidney disease. J Vet Pharmacol Ther 2020; 43:243-267. [PMID: 32128854 PMCID: PMC8614124 DOI: 10.1111/jvp.12848] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2019] [Revised: 01/20/2020] [Accepted: 02/09/2020] [Indexed: 12/24/2022]
Abstract
There is a growing body of experimental and clinical evidence supporting mineralocorticoid receptor (MR) activation as a powerful mediator of renal damage in laboratory animals and humans. Multiple pathophysiological mechanisms are proposed, with the strongest evidence supporting aldosterone-induced vasculopathy, exacerbation of oxidative stress and inflammation, and increased growth factor signalling promoting fibroblast proliferation and deranged extracellular matrix homeostasis. Further involvement of the MR is supported by extensive animal model experiments where MR antagonists (such as spironolactone and eplerenone) abrogate renal injury, including ischaemia-induced damage. Additionally, clinical trials have shown MR antagonists to be beneficial in human chronic kidney disease (CKD) in terms of reducing proteinuria and cardiovascular events, though current studies have not evaluated primary end points which allow conclusions to made about whether MR antagonists reduce mortality or slow CKD progression. Although differences between human and feline CKD exist, feline CKD shares many characteristics with human disease including tubulointerstitial fibrosis. This review evaluates the evidence for the role of the MR in renal injury and summarizes the literature concerning aldosterone in feline CKD. MR antagonists may represent a promising therapeutic strategy in feline CKD.
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Affiliation(s)
- Sarah Spencer
- Comparative Biomedical SciencesThe Royal Veterinary CollegeLondonUK
| | | | - Jonathan Elliott
- Comparative Biomedical SciencesThe Royal Veterinary CollegeLondonUK
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15
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Nutraceutical support in heart failure: a position paper of the International Lipid Expert Panel (ILEP). Nutr Res Rev 2020; 33:155-179. [PMID: 32172721 DOI: 10.1017/s0954422420000049] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
Abstract
Heart failure (HF) is a complex clinical syndrome that represents a major cause of morbidity and mortality in Western countries. Several nutraceuticals have shown interesting clinical results in HF prevention as well as in the treatment of the early stages of the disease, alone or in combination with pharmacological therapy. The aim of the present expert opinion position paper is to summarise the available clinical evidence on the role of phytochemicals in HF prevention and/or treatment that might be considered in those patients not treated optimally as well as in those with low therapy adherence. The level of evidence and the strength of recommendation of particular HF treatment options were weighed up and graded according to predefined scales. A systematic search strategy was developed to identify trials in PubMed (January 1970 to June 2019). The terms 'nutraceuticals', 'dietary supplements', 'herbal drug' and 'heart failure' or 'left verntricular dysfunction' were used in the literature search. The experts discussed and agreed on the recommendation levels. Available clinical trials reported that the intake of some nutraceuticals (hawthorn, coenzyme Q10, l-carnitine, d-ribose, carnosine, vitamin D, probiotics, n-3 PUFA and beet nitrates) might be associated with improvements in self-perceived quality of life and/or functional parameters such as left ventricular ejection fraction, stroke volume and cardiac output in HF patients, with minimal or no side effects. Those benefits tended to be greater in earlier HF stages. Available clinical evidence supports the usefulness of supplementation with some nutraceuticals to improve HF management in addition to evidence-based pharmacological therapy.
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16
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Kilmister EJ, Paterson C, Brasch HD, Davis PF, Tan ST. The Role of the Renin-Angiotensin System and Vitamin D in Keloid Disorder-A Review. Front Surg 2019; 6:67. [PMID: 32039229 PMCID: PMC6988818 DOI: 10.3389/fsurg.2019.00067] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2019] [Accepted: 11/13/2019] [Indexed: 12/20/2022] Open
Abstract
Keloid disorder (KD) is a fibroproliferative condition characterized by excessive dermal collagen deposition in response to wounding and/or inflammation of the skin. Despite intensive research, treatment for KD remains empirical and unsatisfactory. Activation of the renin-angiotensin system (RAS) leads to fibrosis in various organs through its direct effect and the resultant hypertension, and activation of the immune system. The observation of an increased incidence of KD in dark-skinned individuals who are predisposed to vitamin D deficiency (VDD) and hypertension, and the association of KD with hypertension and VDD, all of which are associated with an elevated activity of the RAS, provides clues to the pathogenesis of KD. There is increasing evidence implicating embryonic-like stem (ESC) cells that express ESC markers within keloid-associated lymphoid tissues (KALTs) in keloid lesions. These primitive cells express components of the RAS, cathepsins B, D, and G that constitute bypass loops of the RAS, and vitamin D receptor (VDR). This suggests that the RAS directly, and through signaling pathways that converge on the RAS, including VDR-mediated mechanisms and the immune system, may play a critical role in regulating the primitive population within the KALTs. This review discusses the role of the RAS, its relationship with hypertension, vitamin D, VDR, VDD, and the immune system that provide a microenvironmental niche in regulating the ESC-like cells within the KALTs. These ESC-like cells may be a novel therapeutic target for the treatment of this enigmatic and challenging condition, by modulating the RAS using inhibitors of the RAS and its bypass loops and convergent signaling pathways.
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Affiliation(s)
| | | | - Helen D Brasch
- Gillies McIndoe Research Institute, Wellington, New Zealand
| | - Paul F Davis
- Gillies McIndoe Research Institute, Wellington, New Zealand
| | - Swee T Tan
- Gillies McIndoe Research Institute, Wellington, New Zealand.,Wellington Regional Plastic, Maxillofacial & Burns Unit, Hutt Hospital, Wellington, New Zealand
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17
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Baranowski A, Schlemmer L, Förster K, Slotina E, Mickan T, Truffel S, Klein A, Mattyasovszky SG, Hofmann A, Ritz U, Rommens PM. Effects of losartan and atorvastatin on the development of early posttraumatic joint stiffness in a rat model. Drug Des Devel Ther 2019; 13:2603-2618. [PMID: 31440039 PMCID: PMC6679684 DOI: 10.2147/dddt.s204135] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2019] [Accepted: 06/27/2019] [Indexed: 12/19/2022] Open
Abstract
BACKGROUND After a trauma, exuberant tissue healing with fibrosis of the joint capsule can lead to posttraumatic joint stiffness (PTJS). Losartan and atorvastatin have both shown their antifibrotic effects in different organ systems. OBJECTIVE The purpose of this study was the evaluation of the influence of losartan and atorvastatin on the early development of joint contracture. In addition to joint angles, the change in myofibroblast numbers and the distribution of bone sialoprotein (BSP) were assessed. STUDY DESIGN AND METHODS In this randomized and blinded experimental study with 24 rats, losartan and atorvastatin were compared to a placebo. After an initial joint injury, rat knees were immobilized with a Kirschner wire. Rats received either losartan, atorvastatin or a placebo orally daily. After 14 days, joint angle measurements and histological assessments were performed. RESULTS Losartan increased the length of the inferior joint capsule. Joint angle and other capsule length measurements did not reveal significant differences between both drugs and the placebo. At cellular level both losartan and atorvastatin reduced the total number of myofibroblasts (losartan: 191±77, atorvastatin: 98±58, placebo: 319±113 per counting field, p<0.01) and the percentage area of myofibroblasts (losartan: 2.8±1.8% [p<0.05], atorvastatin: 2.5±1.7% [p<0.01], vs control [6.4±4%], respectively). BSP was detectable in equivalent amounts in the joint capsules of all groups with only a trend toward a reduction of the BSP-stained area by atorvastatin. CONCLUSION Both atorvastatin and losartan reduced the number of myofibroblasts in the posterior knee joint capsule of rat knees 2 weeks after trauma and losartan increased the length of the inferior joint capsule. However, these changes at the cellular level did not translate an increase in range of motion of the rats´ knee joints during early contracture development.
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Affiliation(s)
- Andreas Baranowski
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
| | - Ludwig Schlemmer
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
| | - Katharina Förster
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
| | - Ekaterina Slotina
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
| | - Tim Mickan
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
| | - Sebastian Truffel
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
| | - Anja Klein
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
| | - Stefan G Mattyasovszky
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
| | - Alexander Hofmann
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
- Department of Traumatology and Orthopaedics 1, Westpfalz-Medical Centre Kaiserslautern, Kaiserslautern, Germany
| | - Ulrike Ritz
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
| | - Pol M Rommens
- Department of Orthopaedics and Traumatology, Biomatics Group, University Medical Centre of the Johannes Gutenberg University, Mainz, Germany
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18
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Li Y, Wu C, Gu J, Li D, Yang Y. A novel mutation associated with Type III Bartter syndrome: A report of five cases. Mol Med Rep 2019; 20:65-72. [PMID: 31115572 DOI: 10.3892/mmr.2019.10255] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2018] [Accepted: 02/06/2019] [Indexed: 11/05/2022] Open
Abstract
The clinical, biochemical and mutation spectra of Chinese patients with Type III Bartter syndrome (type III BS), a rare autosomal recessive disorder, were investigated. A total of five unrelated Chinese patients aged 8 months to 24 years were diagnosed with type III BS via analysis of biochemical markers, including chloride, potassium and calcium, and genetic sequencing. The levels of insulin‑like growth factor‑1 (IGF‑1) were evaluated via ELISA and a mutation study of cultured amniocytes was conducted for prenatal diagnosis. The child patients were admitted for polydipsia, polyuria, myasthenia and developmental delay, whereas the adult patients were hospitalized for limb numbness, polydipsia and polyuria. Nine variants in the chloride voltage‑gated channel Kb (CLCNKB) gene were detected, including eight sequence variants and one whole CLCNKB gene deletion. One sequence variant (c.1967T>C) was novel, whereas the remaining variants (c.595G>T, c.908A>C, c.1004T>C, c.1312C>T, c.1334_1335delCT and c.1718C>A) and the whole gene deletion had been previously reported. The whole gene deletion was frequently observed in patients with early‑onset type III BS in the present study. Two patients showed IGF‑1 deficiency with normal growth hormone level. All patients were treated with potassium supplementation and indometacin. The mother of one patient underwent amniocentesis during her second pregnancy; the fetus was not affected by type III BS based on screening for sequence variants, and normal development and blood electrolyte analysis following birth confirmed the diagnosis. In conclusion, five cases of type III BS in patients from mainland China were reported. Large deletions were frequently detected, particularly in early‑onset patients; isolated IGF‑1 deficiency was found, one novel sequence variant was identified. Prenatal diagnosis was successfully established using genetic analysis of cultured amniocytes, and may facilitate the prevention of congenital defect of type III BS in the next pregnancy.
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Affiliation(s)
- Yanhan Li
- Department of Laboratory Animal Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P.R. China
| | - Chengcheng Wu
- Department of Cardiology, General Hospital of Tianjin Medical University, Tianjin 300052, P.R. China
| | - Jie Gu
- Department of Laboratory Animal Center, Institute of Hematology and Blood Diseases Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Tianjin 300020, P.R. China
| | - Dong Li
- Department of Nephrology, General Hospital of Tianjin Medical University, Tianjin 300052, P.R. China
| | - Yanling Yang
- Department of Pediatrics, Peking University First Hospital, Beijing 100034, P.R. China
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19
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Barrera-Chimal J, Girerd S, Jaisser F. Mineralocorticoid receptor antagonists and kidney diseases: pathophysiological basis. Kidney Int 2019; 96:302-319. [PMID: 31133455 DOI: 10.1016/j.kint.2019.02.030] [Citation(s) in RCA: 151] [Impact Index Per Article: 25.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2018] [Revised: 02/04/2019] [Accepted: 02/20/2019] [Indexed: 12/13/2022]
Abstract
Chronic kidney disease (CKD) represents a global health concern, and its prevalence is increasing. The ultimate therapeutic option for CKD is kidney transplantation. However, the use of drugs that target specific pathways to delay or halt CKD progression, such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, and sodium-glucose co-transporter-2 (SGLT-2) inhibitors is limited in clinical practice. Mineralocorticoid receptor activation in nonclassical tissues, such as the endothelium, smooth muscle cells, inflammatory cells, podocytes, and fibroblasts may have deleterious effects on kidney structure and function. Several preclinical studies have shown that mineralocorticoid receptor antagonists (MRAs) ameliorate or cure kidney injury and dysfunction in different models of kidney disease. In this review, we present the preclinical evidence showing a benefit of MRAs in acute kidney injury, the transition from acute kidney injury to CKD, hypertensive and diabetic nephropathy, glomerulonephritis, and kidney toxicity induced by calcineurin inhibitors. We also discuss the molecular mechanisms responsible for renoprotection related to MRAs that lead to reduced oxidative stress, inflammation, fibrosis, and hemodynamic alterations. The available clinical data support a benefit of MRA in reducing proteinuria in diabetic kidney disease and improving cardiovascular outcomes in CKD patients. Moreover, a benefit of MRAs in kidney transplantation has also been observed. The past and present clinical trials describing the effect of MRAs on kidney injury are presented, and the risk of hyperkalemia and use of other options, such as potassium binding agents or nonsteroidal MRAs, are also addressed. Altogether, the available preclinical and clinical data support a benefit of using MRAs in CKD, an approach that should be further explored in future clinical trials.
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Affiliation(s)
- Jonatan Barrera-Chimal
- Laboratorio de Fisiología Cardiovascular y Trasplante Renal, Unidad de Medicina Traslacional, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México and Instituto Nacional de Cardiología Ignacio Chávez, Mexico City, Mexico
| | - Sophie Girerd
- Transplant Unit, Nephrology Department, Nancy University Hospital, Lorraine University, Vandoeuvre-lès-Nancy, France; Institut national de la santé et de la recherche médicale U1116, Clinical Investigation Centre, Lorraine University, Vandoeuvre-lès-Nancy, France; Investigation Network Initiative - Cardiovascular and Renal Clinical Trialists, French-Clinical Research Infrastructure Network, Nancy, France
| | - Frederic Jaisser
- Institut national de la santé et de la recherche médicale U1116, Clinical Investigation Centre, Lorraine University, Vandoeuvre-lès-Nancy, France; Investigation Network Initiative - Cardiovascular and Renal Clinical Trialists, French-Clinical Research Infrastructure Network, Nancy, France; Institut national de la santé et de la recherche médicale, UMRS 1138, Team 1, Centre de Recherche des Cordeliers, Sorbonne University, Paris Descartes University, Paris, France.
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20
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Abstract
Aldosterone is a mineralocorticoid hormone, as its main renal effect has been considered as electrolyte and water homeostasis in the distal tubule, thus maintaining blood pressure and extracellular fluid homeostasis through the activation of mineralocorticoid receptor (MR) in epithelial cells. However, over the past decade, numerous studies have documented the significant role of aldosterone in the progression of chronic kidney disease (CKD) which has become a subject of interest. It is being studied that aldosterone can affect cardiovascular and renal system, thereby contributing to tissue inflammation, injury, glomerulosclerosis, and interstitial fibrosis. Aldosterone acts on renal vessels, renal cells (glomerular mesangial cells, podocytes, vascular smooth muscle cells, tubular epithelial cells, and interstitial fibroblasts), and infiltrating inflammatory cells, inducing reactive oxygen species (ROS) production, upregulated epithelial growth factor receptor (EGFR), and type 1 angiotensin (AT1) receptor expressions, and activating nuclear factor kappa B (NF-κB), activator protein-1 (AP-1), and EGFR to further promote cell proliferation, apoptosis, and proliferation. Phenotypic transformation of epithelial cells stimulates the expression of transforming growth factor-β (TGF-β), connective tissue growth factor (CTGF), osteopontin (OPN), and plasminogen activator inhibitor-1 (PAI-1), eventually leading to renal fibrosis. MR antagonisms are related to inhibition of aldosterone-mediated pro-inflammatory and pro-fibrotic effect. In this review, we will summarize the important role of aldosterone in the pathogenesis of renal injury and fibrosis, emphasizing on its multiple underlying mechanisms and advances in aldosterone research along with the potential therapeutics for targeting MR in a renal fibrosis.
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21
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Firoozmand LT, Sanches A, Damaceno-Rodrigues NR, Perez JD, Aragão DS, Rosa RM, Marcondes FK, Casarini DE, Caldini EG, Cunha TS. Blockade of AT1 type receptors for angiotensin II prevents cardiac microvascular fibrosis induced by chronic stress in Sprague-Dawley rats. Stress 2018; 21:484-493. [PMID: 29676198 DOI: 10.1080/10253890.2018.1462328] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
To test the effects of chronic-stress on the cardiovascular system, the model of chronic mild unpredictable stress (CMS) has been widely used. The CMS protocol consists of the random, intermittent, and unpredictable exposure of laboratory animals to a variety of stressors, during 3 consecutive weeks. In this study, we tested the hypothesis that exposure to the CMS protocol leads to left ventricle microcirculatory remodeling that can be attenuated by angiotensin II receptor blockade. Male Sprague-Dawley rats were randomly assigned into four groups: Control, Stress, Control + losartan, and Stress + losartan (N = 6, each group, losartan: 20 mg/kg/day). The rats were euthanized 15 days after CMS exposure, and blood samples and left ventricle were collected. Rats submitted to CMS presented increased glycemia, corticosterone, noradrenaline and adrenaline concentration, and losartan reduced the concentration of the circulating amines. Cardiac angiotensin II, measured by high-performance liquid chromatography (HPLC), was significantly increased in the CMS group, and losartan treatment reduced it, while angiotensin 1-7 was significantly higher in the CMS losartan-treated group as compared with CMS. Histological analysis, verified by transmission electron microscopy, showed that rats exposed to CMS presented increased perivascular collagen and losartan effectively prevented the development of this process. Hence, CMS induced a state of microvascular disease, with increased perivascular collagen deposition, that may be the trigger for further development of cardiovascular disease. In this case, CMS fibrosis is associated with increased production of catecholamines and with a disruption of renin-angiotensin system balance, which can be prevented by angiotensin II receptor blockade.
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Affiliation(s)
| | - Andrea Sanches
- Department of Physiological Sciences, Piracicaba Dental School, University of Campinas (FOP-UNICAMP), Piracicaba, Brazil
| | - Nilsa Regina Damaceno-Rodrigues
- Laboratory of Cell Biology (LIM59), Department of Pathology, School of Medicine, University of São Paulo (USP), São Paulo, Brazil
| | - Juliana Dinéia Perez
- Department of Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | | | - Rodolfo Mattar Rosa
- Department of Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Fernanda Klein Marcondes
- Department of Physiological Sciences, Piracicaba Dental School, University of Campinas (FOP-UNICAMP), Piracicaba, Brazil
| | - Dulce Elena Casarini
- Department of Medicine, Federal University of São Paulo (UNIFESP), São Paulo, Brazil
| | - Elia Garcia Caldini
- Laboratory of Cell Biology (LIM59), Department of Pathology, School of Medicine, University of São Paulo (USP), São Paulo, Brazil
| | - Tatiana Sousa Cunha
- Institute of Science and Technology, Department of Science and Technology, Federal University of São Paulo (UNIFESP), São José dos Campos, Brazil
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Sun J, Zhao F, Zhang W, Lv J, Lv J, Yin A. BMSCs and miR-124a ameliorated diabetic nephropathy via inhibiting notch signalling pathway. J Cell Mol Med 2018; 22:4840-4855. [PMID: 30024097 PMCID: PMC6156290 DOI: 10.1111/jcmm.13747] [Citation(s) in RCA: 45] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2017] [Accepted: 06/01/2018] [Indexed: 02/06/2023] Open
Abstract
BMSCs are important in replacement therapy of diabetic nephropathy (DN). MiR‐124a exerts effect on the differentiation capability of pancreatic progenitor cells. The objective of this study was to explore the molecular mechanisms, the functions of miR‐124a and bone marrow mesenchymal stem cells (BMSCs) in the treatment of DN. Characterizations of BMSCs were identified using the inverted microscope and flow cytometer. The differentiations of BMSCs were analysed by immunofluorescence assay and DTZ staining. The expression levels of islet cell‐specific transcription factors, apoptosis‐related genes, podocytes‐related genes and Notch signalling components were detected using quantitative real‐time reverse transcription PCR (qRT‐PCR) and Western blot assays. The production of insulin secretion was detected by adopting radioimmunoassay. Cell proliferation and apoptosis abilities were detected by CCK‐8, flow cytometry and TUNEL assays. We found that BMSCs was induced into islet‐like cells and that miR‐124a could promote the BMSCs to differentiate into islet‐like cells. BMSCs in combination with miR‐124a regulated islet cell‐specific transcription factors, apoptosis‐related genes, podocytes‐related genes as well as the activity of Notch signalling pathway. However, BMSCs in combination with miR‐124a relieved renal lesion caused by DN and decreased podocyte apoptosis caused by HG. The protective effect of BMSCs in combination with miR‐124a was closely related to the inactivation of Notch signalling pathway. MSCs in combination with miR‐124a protected kidney tissue from impairment and inhibited nephrocyte apoptosis in DN.
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Affiliation(s)
- Jiping Sun
- Department of Nephrology, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Fei Zhao
- Department of Obstetrics and Gynecology, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Wenjing Zhang
- Department of Nephrology, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Jia Lv
- Department of Nephrology, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Jing Lv
- Department of Nephrology, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China
| | - Aiping Yin
- Department of Nephrology, the First Affiliated Hospital of Medical College, Xi'an Jiaotong University, Xi'an, China
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Mohammadi AA, Parand A, Kardeh S, Janati M, Mohammadi S. Efficacy of Topical Enalapril in Treatment of Hypertrophic Scars. World J Plast Surg 2018; 7:326-331. [PMID: 30560072 PMCID: PMC6290307 DOI: 10.29252/wjps.7.3.326] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
BACKGROUND Angiotensin II activation by angiotensin-converting enzyme (ACE) is a significant mediator in wound healing and collagen production. In this study, the effect of topical application of ACE on hypertrophic scar formation has been studied in a clinical trial. METHODS Thirty patients with hypertrophic scar and itching after treatment of 2nd or 3rd degree burns participated in this double-blinded clinical trial. Subjects had two same-degree scars on symmetrical sites of body which were randomly allocated into two groups. One side was treated with 1% enalapril ointment and the other side with placebo twice daily. During a 6-months follow-up, a scoring table for itching was completed on a daily basis by patients. Furthermore, a single surgeon measured size of scars once a month. The mean size, thickness and itching score were calculated for each scar and compared between medication and placebo-treated scars. RESULTS The mean size of scars in enalapril treated side was significantly less than scars in the placebo side. Additionally, enalapril treated scars had significantly lower itching scores compared to the placebo group. CONCLUSION Topical enalapril significantly decreases the clinical parameters of hypertrophic scar and also itching as an indirect indicative of scar improvement. Furthermore, enalapril proved to be clinically safe for patients with low incidence of adverse drug reactions and acceptable cost effectiveness.
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Affiliation(s)
- Ali Akbar Mohammadi
- Burn and Wound Healing Research Center, Division of Plastic and Reconstructive Surgery, Department of Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Ali Parand
- Burn and Wound Healing Research Center, Division of Plastic and Reconstructive Surgery, Department of Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Sina Kardeh
- Burn and Wound Healing Research Center, Division of Plastic and Reconstructive Surgery, Department of Surgery, Shiraz University of Medical Sciences, Shiraz, Iran.,Student Research Committee, Shiraz University of Medical Sciences, Shiraz, Iran.,Cell and Molecular Medicine Student Research Group, Shiraz School of Medicine, Shiraz, Iran
| | - Mansour Janati
- Department of Cardiac Surgery, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Soheil Mohammadi
- Faculty of Medicine,Tehran University of Medical Sciences, Tehran, Iran
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24
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Nishihara M, Takesue K, Hirooka Y. Olmesartan combined with renal denervation reduces blood pressure in association with sympatho-inhibitory and aldosterone-reducing effects in hypertensive mice with chronic kidney disease. Clin Exp Hypertens 2018; 41:211-219. [DOI: 10.1080/10641963.2018.1465075] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
Affiliation(s)
- Masaaki Nishihara
- Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Ko Takesue
- Department of Cardiovascular Medicine, Kyushu University Graduate School of Medical Sciences, Fukuoka, Japan
| | - Yoshitaka Hirooka
- Department of Advanced Cardiovascular Regulation and Therapeutics, Kyushu University, Fukuoka, Japan
- Department of Medical Science Technology, International University of Health and Welfare School of Health Sciences at Fukuoka, Okawa City, Japan
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25
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Yang X, Zhang G, Wang M, Yang H, Li Q. Bartter Syndrome Type 3: Phenotype-Genotype Correlation and Favorable Response to Ibuprofen. Front Pediatr 2018; 6:153. [PMID: 29900164 PMCID: PMC5989644 DOI: 10.3389/fped.2018.00153] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2017] [Accepted: 05/08/2018] [Indexed: 12/19/2022] Open
Abstract
Objective: To investigate the phenotype-genotype correlation in different genetic kinds of Bartter syndrome type 3 in children. Methods: Clinical and genetic data of 2 patients with different mutations in Bartter syndrome type 3 was analyzed while the prognosis was compared after a 6-year follow-up or 2-year follow-up, respectively. Results: Bartter syndrome is a kind of autosomal recessive inherited renal disorder. The manifestation and prognosis of Bartter syndrome change with mutation types, and severe mutation were often accompanied with unfavorable prognosis. Comprehensive therapy with ibuprofen, antisterone, captopril, and potassium have remarkable effect, while ibuprofen may improve growth retardation partly. Conclusion: Bartter syndrome should be considered when children have unreasonable continuous electrolyte disturbance, metabolic alkalosis and growth retardation.As a genetic disease, its clinical features depend on the mutation type. It can be ameliorated by electrolyte supplementation, prostaglandin synthetase inhibitors, angiotensin-converting enzyme inhibitors and potassium-sparing diuretic. Considering the following electrolyte disturbances, infections, growth retardation, kidney failure and even death, Bartter syndrome need lifelong treatment, early diagnosis and treatment is the most important.
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Affiliation(s)
- Xuejun Yang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Gaofu Zhang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Mo Wang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Haiping Yang
- Department of Nephrology, Children's Hospital of Chongqing Medical University, Chongqing, China
| | - Qiu Li
- Department of Nephrology, Children's Hospital of Chongqing Medical University, Chongqing, China
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26
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Beenken A, Bomback AS. Aldosterone breakthrough does not alter central hemodynamics. J Renin Angiotensin Aldosterone Syst 2017; 18:1470320317735002. [PMID: 28992758 PMCID: PMC5843861 DOI: 10.1177/1470320317735002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022] Open
Abstract
Introduction: Angiotensin-converting enzyme inhibitors and angiotensin receptor blockers are widely used in congestive heart failure and chronic kidney disease, but up to 40% of patients will experience aldosterone breakthrough, with aldosterone levels rising above pre-treatment levels after 6–12 months of renin-angiotensin-aldosterone system blockade. Aldosterone breakthrough has been associated with worsening congestive heart failure and chronic kidney disease, yet the pathophysiology remains unclear. Breakthrough has not been associated with elevated peripheral blood pressure, but no studies have assessed its effect on central blood pressure. Methods: Nineteen subjects with well-controlled peripheral blood pressure on stable doses of angiotensin-converting enzyme inhibitor/angiotensin receptor blocker had aldosterone levels checked and central blood pressure parameters measured using the SphygmoCor system. The central blood pressure parameters of subjects with or without breakthrough, defined as serum aldosterone >15 ng/dl, were compared. Results: Of the 19 subjects, six had breakthrough with a mean aldosterone level of 33.8 ng/dl, and 13 were without breakthrough with a mean level of 7.1 ng/dl. There was no significant difference between the two groups in any central blood pressure parameter. Conclusions: We found no correlation between aldosterone breakthrough and central blood pressure. The clinical impact of aldosterone breakthrough likely depends on its non-genomic, pro-fibrotic, pro-inflammatory effects rather than its regulation of extracellular volume.
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Affiliation(s)
- Andrew Beenken
- Department of Medicine, Division of Nephrology, Columbia University Medical Center, New York, NY, USA
| | - Andrew S Bomback
- Department of Medicine, Division of Nephrology, Columbia University Medical Center, New York, NY, USA
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27
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β-Adrenergic Receptor Blockers Reduce the Occurrence of Keloids and Hypertrophic Scars after Cardiac Device Implantation. Plast Reconstr Surg 2017; 139:1248-1256. [DOI: 10.1097/prs.0000000000003239] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
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28
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Current Understanding of the Pathogenesis of Progressive Chronic Kidney Disease in Cats. Vet Clin North Am Small Anim Pract 2016; 46:1015-48. [PMID: 27461408 DOI: 10.1016/j.cvsm.2016.06.002] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
In cats with chronic kidney disease (CKD), the most common histopathologic finding is tubulointerstitial inflammation and fibrosis. However, these changes reflect a nonspecific response of the kidney to any inciting injury. The risk of developing CKD is likely to reflect the composite effects of genetic predisposition, aging, and environmental and individual factors that affect renal function over the course of a cat's life. However, there is still little information available to determine exactly which individual risk factors predispose a cat to develop CKD. Although many cats diagnosed with CKD have stable disease for years, some cats show overtly progressive disease.
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29
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Pitt B, Stier CT, Rajagopalan S. Mineralocorticoid receptor blockade: new insights into the mechanism of action in patients with cardiovascular disease. J Renin Angiotensin Aldosterone Syst 2016; 4:164-8. [PMID: 14608520 DOI: 10.3317/jraas.2003.025] [Citation(s) in RCA: 42] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
Mineralocorticoid receptor (MR) blockade is effective in reducing total mortality and the incidence of heart failure in patients with systolic left ventricular dysfunction (SLVD) associated with chronic heart failure or post myocardial infarction. Pre-clinical and clinical studies in SLVD have shown that MR blockade reduces sudden cardiac death, left ventricular remodelling, left ventricular hypertrophy, endothelial dysfunction, autonomic imbalance, renal dysfunction and improves fibrinolysis. While MR blockade promotes sodium excretion and the combination of an angiotensin-converting enzyme inhibitor and a MR blocker have been shown to be more effective than either alone in causing natriuresis, it is unlikely that their beneficial effects can be explained solely on this basis. Aldosterone has been shown to have a number of adverse effects, including activation of other neurohumeral mediators, stimulation of active reactive oxygen species (ROS), activation of the NF-κβ and AP-1 signalling pathways, vascular inflammation and fibrosis, myocardial hypertrophy, autonomic imbalance, and a decrease in fibrinolysis. MR blockade is, however, effective both in situations with and without an increase in serum aldosterone level, since the MR can be occupied and activated by cortisol as well as by aldosterone. In view of these mechanisms, MR blockade may play an important role not only on SLVD, but also in essential hypertension with normal systolic function, diastolic heart failure, valvular heart disease, vascular stiffening with ageing, progression of renal disease, and diabetes mellitus. This hypothesis will, however, require further prospective evaluation.
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Affiliation(s)
- Bertram Pitt
- Division of Cardiology, University of Michigan, USA.
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30
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Muñoz-Durango N, Fuentes CA, Castillo AE, González-Gómez LM, Vecchiola A, Fardella CE, Kalergis AM. Role of the Renin-Angiotensin-Aldosterone System beyond Blood Pressure Regulation: Molecular and Cellular Mechanisms Involved in End-Organ Damage during Arterial Hypertension. Int J Mol Sci 2016; 17:E797. [PMID: 27347925 PMCID: PMC4964362 DOI: 10.3390/ijms17070797] [Citation(s) in RCA: 167] [Impact Index Per Article: 18.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/24/2016] [Revised: 05/02/2016] [Accepted: 05/10/2016] [Indexed: 01/07/2023] Open
Abstract
Arterial hypertension is a common condition worldwide and an important predictor of several complicated diseases. Arterial hypertension can be triggered by many factors, including physiological, genetic, and lifestyle causes. Specifically, molecules of the renin-angiotensin-aldosterone system not only play important roles in the control of blood pressure, but they are also associated with the genesis of arterial hypertension, thus constituting a need for pharmacological interventions. Chronic high pressure generates mechanical damage along the vascular system, heart, and kidneys, which are the principal organs affected in this condition. In addition to mechanical stress, hypertension-induced oxidative stress, chronic inflammation, and the activation of reparative mechanisms lead to end-organ damage, mainly due to fibrosis. Clinical trials have demonstrated that renin-angiotensin-aldosterone system intervention in hypertensive patients lowers morbidity/mortality and inflammatory marker levels as compared to placebo patients, evidencing that this system controls more than blood pressure. This review emphasizes the detrimental effects that a renin-angiotensin-aldosterone system (RAAS) imbalance has on health considerations above and beyond high blood pressure, such as fibrotic end-organ damage.
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Affiliation(s)
- Natalia Muñoz-Durango
- Millenium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, 8330025 Santiago, Chile.
| | - Cristóbal A Fuentes
- Millenium Institute on Immunology and Immunotherapy, Departamento de Endocrinología, Escuela de Medicina, Pontificia Universidad Católica de Chile, 8330074 Santiago, Chile.
| | - Andrés E Castillo
- Millenium Institute on Immunology and Immunotherapy, Departamento de Endocrinología, Escuela de Medicina, Pontificia Universidad Católica de Chile, 8330074 Santiago, Chile.
| | - Luis Martín González-Gómez
- Millenium Institute on Immunology and Immunotherapy, Departamento de Endocrinología, Escuela de Medicina, Pontificia Universidad Católica de Chile, 8330074 Santiago, Chile.
| | - Andrea Vecchiola
- Millenium Institute on Immunology and Immunotherapy, Departamento de Endocrinología, Escuela de Medicina, Pontificia Universidad Católica de Chile, 8330074 Santiago, Chile.
| | - Carlos E Fardella
- Millenium Institute on Immunology and Immunotherapy, Departamento de Endocrinología, Escuela de Medicina, Pontificia Universidad Católica de Chile, 8330074 Santiago, Chile.
| | - Alexis M Kalergis
- Millenium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, 8330025 Santiago, Chile.
- Millenium Institute on Immunology and Immunotherapy, Departamento de Endocrinología, Escuela de Medicina, Pontificia Universidad Católica de Chile, 8330074 Santiago, Chile.
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Sangaralingham SJ, Wang BH, Huang L, Kumfu S, Ichiki T, Krum H, Burnett JC. Cardiorenal fibrosis and dysfunction in aging: Imbalance in mediators and regulators of collagen. Peptides 2016; 76:108-14. [PMID: 26774586 PMCID: PMC4754975 DOI: 10.1016/j.peptides.2016.01.004] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/12/2015] [Revised: 12/19/2015] [Accepted: 01/08/2016] [Indexed: 01/01/2023]
Abstract
Cardiorenal fibrosis is a biological process that increases with age and contributes to dysfunction of the heart and kidney. While numerous circulating and tissue hormones, cytokines and enzymes have been identified in the development of cardiorenal fibrosis, several reports have suggested that the anti-fibrotic natriuretic peptide system (NPS), pro-fibrotic renin-angiotensin-aldosterone system (RAAS), transforming growth factor-beta 1 (TGF-β1), matrix metalloproteinases (MMPs) and tissue inhibitor of metalloproteinases (TIMPs) are fundamental regulators and mediators of this process. However, the simultaneous assessment of these components in the development of age-mediated cardiorenal fibrotic remodeling is not completely understood. Thus, we assessed cardiorenal structure and function, the circulating NPS and RAAS and the cardiorenal tissue gene expression of collagen (Col) I, Col III, TGF-β1, MMP-9 and TIMP-1 in 2 and 20 month old Fischer rats. Our studies determined that aging was characterized by an increase in cardiorenal fibrosis that was accompanied with cardiorenal dysfunction. These alterations were associated with lower circulating atrial and C-type natriuretic peptides and higher angiotensin II and aldosterone levels in the aged rats. Moreover, we observed a decrease in Col I and III and an increase in TIMP- mRNA expressions in the aged heart and kidney, while TGF-β1 expression increased and MMP-9 decreased only in the aged kidney. We conclude that the age-mediated alterations in these fibrotic regulator and mediator profiles favors collagen accumulation due to an imbalance between the NPS and RAAS as well as a decline in the degradative pathway, thus suggesting a therapeutic opportunity to target these components.
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Affiliation(s)
- S Jeson Sangaralingham
- Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA.
| | - Bing H Wang
- Centre of Cardiovascular Research and Education in Therapeutics, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
| | - Li Huang
- Centre of Cardiovascular Research and Education in Therapeutics, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
| | - Sirinart Kumfu
- Centre of Cardiovascular Research and Education in Therapeutics, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
| | - Tomoko Ichiki
- Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
| | - Henry Krum
- Centre of Cardiovascular Research and Education in Therapeutics, School of Epidemiology and Preventive Medicine, Monash University, Melbourne, Australia
| | - John C Burnett
- Cardiorenal Research Laboratory, Division of Cardiovascular Diseases, Mayo Clinic, Rochester, MN, USA
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32
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Gu YY, Wang H, Wang S, Gao H, Qiu MC. Effects of Cordyceps sinensis on the Expressions of NF-κB and TGF-β1 in Myocardium of Diabetic Rats. EVIDENCE-BASED COMPLEMENTARY AND ALTERNATIVE MEDICINE : ECAM 2015; 2015:369631. [PMID: 26697096 PMCID: PMC4677184 DOI: 10.1155/2015/369631] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 03/23/2015] [Revised: 07/26/2015] [Accepted: 08/02/2015] [Indexed: 11/17/2022]
Abstract
Objective. To investigate the effect of Cordyceps sinensis (CS) on the expressions of NF-κB and TGF-β1 in myocardium of streptozotocin-induced diabetic rats. Methods. A total of 53 healthy male SD rats, mice age of 8 weeks and weight of 220 ± 20 g, were randomly divided into five groups by randomized block design: normal control group (n = 10), diabetic group (n = 10), low dose of CS group (n = 12; CS 0.6 g·kg(-1)·d(-1)), middle dose of CS group (n = 11; CS 2.5 g·kg(-1)·d(-1)), and high dose of CS group (n = 10; CS 5 g·kg(-1)·d(-1)). The diabetic models with tail intravenous injection by streptozotocin (45 mg·kg(-1)). Diabetic rats were sacrificed after 8 weeks; the expressions of NF-κB and TGF-β1 proteins and mRNA in the cardiac muscle were determined by using immunohistochemistry staining and reverse transcription polymerase chain reaction (RT-PCR) method. The data were analyzed using one factor analysis of variance. Result. The expressions of NF-κB and TGF-β1 proteins and mRNA in the cardiac muscle of diabetic rats were significantly raised (P < 0.05), which could be decreased by CS (P < 0.05). Conclusions. The changes on the expressions of NF-κB and TGF-β1 in myocardium may be involved in the occurrence of diabetic cardiomyopathy (DC). CS may play its role on myocardial protection by regulating the expressions of NF-κB and TGF-β1 in myocardium.
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Affiliation(s)
- You-you Gu
- Department of Endocrinology, The Fifth Central Hospital of Tianjin, Tianjin 300450, China
| | - Huan Wang
- Community Health Service Center of Hu Jiayuan Street, Binhai New District, Tianjin 300454, China
- Graduate School of Tianjin Medical University, Tianjin 300070, China
| | - Su Wang
- Department of Endocrinology, The Fifth Central Hospital of Tianjin, Tianjin 300450, China
| | - Hua Gao
- Department of Endocrinology, General Hospital of Tianjin Medical University, Tianjin 300052, China
| | - Ming-cai Qiu
- Department of Endocrinology, General Hospital of Tianjin Medical University, Tianjin 300052, China
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Guo Z, Huang D, Tang X, Han J, Li J. Correlation between advanced glycation end-products and the expression of fatty inflammatory factors in type II diabetic cardiomyopathy. Bosn J Basic Med Sci 2015; 15:15-9. [PMID: 26614846 DOI: 10.17305/bjbms.2015.619] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Revised: 08/18/2015] [Accepted: 08/18/2015] [Indexed: 11/16/2022] Open
Abstract
Diabetic cardiomyopathy (DCM) is one of the most severe complications of diabetes without a clear pathogenesis. Th is study investigated the adiponectin (APN) and leptin levels in type II DCM, as well as their correlation with advanced glycation end-products (AGEs). From 2011-2013, 78 type II diabetes mellitus (T2DM) cases (40-65 years old) in the Taian region were randomly selected. Based on the results of colour Doppler ultrasonography and coronary angiography, the cases were divided into a simple T2DM group (40 cases) and a DCM group (38 cases). Forty healthy subjects were used as normal control (NC). An enzyme-linked immunosorbent assay was performed to determine the levels of fa tty inflammatory factors such as APN, leptin and AGEs, and a correlation analysis was conducted. In the T2DM group, the APN levels were decreased but the leptin and AGE levels were significantly increased compared to the NC group. In the DCM group, the APN levels were decreased but the leptin and AGE levels were significantly increased (P<0.01) compared to the T2DM group. Th e AGE levels were positively correlated with disease progression and with fasting plasma glucose levels, glycated haemoglobin, insulin resistance and leptin, but were negatively correlated with APN levels. Additionally, the APN and leptin levels were independently related to the AGE levels. Fatty inflammatory factors play a significant role in the progression of both simple T2DM and DCM. Th e results of this study revealed the pathogenesis of DCM and indicated the potential significance of AGEs in DCM prevention and treatment.
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Affiliation(s)
- Zhengdong Guo
- Affiliated Hospital of Taishan Medical University, Tai'an 271000, China.
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Orlic L, Mikolasevic I, Lukenda V, Anic K, Jelic I, Racki S. Nonalcoholic fatty liver disease and the renin-angiotensin system blockers in the patients with chronic kidney disease. Wien Klin Wochenschr 2015; 127:355-362. [PMID: 25412597 DOI: 10.1007/s00508-014-0661-y] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/06/2014] [Accepted: 10/20/2014] [Indexed: 12/11/2022]
Abstract
BACKGROUND Recent data suggest that the renin-angiotensin-aldosteron system (RAAS) may be of importance in the pathogenesis of nonalcoholic fatty liver disease (NAFLD). We were interested to investigate whether the therapy with RAAS blockers in patients with different stages of chronic kidney disease (CKD) has any effect on steatosis and fibrosis grade; NAFLD documented by transient elastography (TE) (Fibroscan(®)-CAP). METHODS Of 191 patients with various stages of CKD there were 61 patients with CKD grade III and IV, 62 patients with end-stage renal disease treated with chronic hemodialysis and 68 renal transplant recipients. Liver stiffness was selected as the parameter to quantify liver fibrosis. Furthermore, the Controlled Attenuation Parameter (CAP) was used to detect and quantify liver steatosis with the help of TE. RESULTS CKD patients (p = 0.005) and CKD-NAFLD patients (p = 0.0005) with angiotensin-converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARBs) had statistically significant lower degree of liver stiffness in comparison to those without these medications (p = 0.005). Also, we were interested to explore is there any difference in fibrosis and steatosis grade due to use of ACE-I or ARBs. We did not find statistically significant differences between those two subgroups of patients with respect to liver steatosis/fibrosis. CONCLUSION Based on our results, RAAS blockers could be an attractive option for the management of NAFLD. We believe that TE provides the opportunity of noninvasive screening of NAFLD in CKD patients. In further prospective analysis, we believe that by using TE as noninvasive method we could investigate are ACE-I/ARBs really effective medications for the treatment of NAFLD in CKD patients.
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Affiliation(s)
- Lidija Orlic
- Department of Nephrology, Dialysis and Kidney Transplantation, University Hospital Center Rijeka, Tome Strižića 3, 51000, Rijeka, Croatia
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Murphy AM, Wong AL, Bezuhly M. Modulation of angiotensin II signaling in the prevention of fibrosis. FIBROGENESIS & TISSUE REPAIR 2015; 8:7. [PMID: 25949522 PMCID: PMC4422447 DOI: 10.1186/s13069-015-0023-z] [Citation(s) in RCA: 117] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 09/08/2014] [Accepted: 03/06/2015] [Indexed: 12/20/2022]
Abstract
Over the last decade, it has become clear that the role of angiotensin II extends far beyond recognized renal and cardiovascular effects. The presence of an autologous renin-angiotensin system has been demonstrated in almost all tissues of the body. It is now known that angiotensin II acts both independently and in synergy with TGF-beta to induce fibrosis via the angiotensin type 1 receptor (AT1) in a multitude of tissues outside of the cardiovascular and renal systems, including pulmonary fibrosis, intra-abdominal fibrosis, and systemic sclerosis. Interestingly, recent studies have described a paradoxically regenerative effect of the angiotensin system via stimulation of the angiotensin type 2 receptor (AT2). Activation of AT2 has been shown to ameliorate fibrosis in animal models of skeletal muscle, gastrointestinal, and neurologic diseases. Clinical reports suggest a beneficial role for modulation of angiotensin II signaling in cutaneous scarring. This article reviews current knowledge on the role that angiotensin II plays in tissue fibrosis, as well as current and potential therapies targeting this system.
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Affiliation(s)
- Amanda M Murphy
- Division of Plastic and Reconstructive Surgery, Dalhousie University, 5850/5980 University Avenue, PO Box 9700, B3K 6R8 Halifax, NS Canada
| | - Alison L Wong
- Division of Plastic and Reconstructive Surgery, Dalhousie University, 5850/5980 University Avenue, PO Box 9700, B3K 6R8 Halifax, NS Canada
| | - Michael Bezuhly
- Division of Plastic and Reconstructive Surgery, Dalhousie University, 5850/5980 University Avenue, PO Box 9700, B3K 6R8 Halifax, NS Canada ; IWK Health Centre, Dalhousie University, 5850/5980 University Avenue, PO Box 9700, B3K 6R8 Halifax, NS Canada
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Garza MA, Wason EA, Zhang JQ. Cardiac remodeling and physical training post myocardial infarction. World J Cardiol 2015; 7:52-64. [PMID: 25717353 PMCID: PMC4325302 DOI: 10.4330/wjc.v7.i2.52] [Citation(s) in RCA: 66] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/29/2014] [Revised: 12/22/2014] [Accepted: 01/19/2015] [Indexed: 02/06/2023] Open
Abstract
After myocardial infarction (MI), the heart undergoes extensive myocardial remodeling through the accumulation of fibrous tissue in both the infarcted and noninfarcted myocardium, which distorts tissue structure, increases tissue stiffness, and accounts for ventricular dysfunction. There is growing clinical consensus that exercise training may beneficially alter the course of post-MI myocardial remodeling and improve cardiac function. This review summarizes the present state of knowledge regarding the effect of post-MI exercise training on infarcted hearts. Due to the degree of difficulty to study a viable human heart at both protein and molecular levels, most of the detailed studies have been performed by using animal models. Although there are some negative reports indicating that post-MI exercise may further cause deterioration of the wounded hearts, a growing body of research from both human and animal experiments demonstrates that post-MI exercise may beneficially alter the course of wound healing and improve cardiac function. Furthermore, the improved function is likely due to exercise training-induced mitigation of renin-angiotensin-aldosterone system, improved balance between matrix metalloproteinase-1 and tissue inhibitor of matrix metalloproteinase-1, favorable myosin heavy chain isoform switch, diminished oxidative stress, enhanced antioxidant capacity, improved mitochondrial calcium handling, and boosted myocardial angiogenesis. Additionally, meta-analyses revealed that exercise-based cardiac rehabilitation has proven to be effective, and remains one of the least expensive therapies for both the prevention and treatment of cardiovascular disease, and prevents re-infarction.
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Rutkowski B, Tylicki L. Nephroprotective action of renin-angiotensin-aldosterone system blockade in chronic kidney disease patients: the landscape after ALTITUDE and VA NEPHRON-D trails. J Ren Nutr 2015; 25:194-200. [PMID: 25576239 DOI: 10.1053/j.jrn.2014.10.026] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2014] [Accepted: 10/29/2014] [Indexed: 01/13/2023] Open
Abstract
The intervention in the renin-angiotensin-aldosterone system (RAAS) is currently the most effective strategy that combines blood pressure lowering and renoprotection. Several large, randomized, controlled trials evidenced the renoprotective potential of the angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs) in nephropathies of almost any etiology. Mineralocorticoid receptor antagonists and direct renin inhibitor, aliskiren, as add-on treatments to standard therapy including the optimal dose of ACEIs or ARBs reduce albuminuria or proteinuria and slow development of renal dysfunction more than placebo. No clinical evidence is available however about whether these strategies may influence on long-term kidney outcome. Three recent trials suggested that aggressive RAAS blockade, that is, combination of 2 RAAS-blocking agents, does not decrease cardiovascular and renal morbidity and may carry an increased risk of serious complications. This article reviews an evidence-based approach on the use of RAAS-inhibiting agents in chronic kidney disease and considers the implementation of dual RAAS blockade with reference to the results of ALTITUDE and VA NEPHRON-D trails aiming to aid clinicians in their treatment decisions for patients with chronic kidney disease.
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Affiliation(s)
- Boleslaw Rutkowski
- Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, Gdańsk, Poland
| | - Leszek Tylicki
- Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdańsk, Gdańsk, Poland.
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Lawson J, Elliott J, Wheeler-Jones C, Syme H, Jepson R. Renal fibrosis in feline chronic kidney disease: known mediators and mechanisms of injury. Vet J 2014; 203:18-26. [PMID: 25475166 DOI: 10.1016/j.tvjl.2014.10.009] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2014] [Revised: 10/10/2014] [Accepted: 10/11/2014] [Indexed: 01/13/2023]
Abstract
Chronic kidney disease (CKD) is a common medical condition of ageing cats. In most cases the underlying aetiology is unknown, but the most frequently reported pathological diagnosis is renal tubulointerstitial fibrosis. Renal fibrosis, characterised by extensive accumulation of extra-cellular matrix within the interstitium, is thought to be the final common pathway for all kidney diseases and is the pathological lesion best correlated with function in both humans and cats. As a convergent pathway, renal fibrosis provides an ideal target for the treatment of CKD and knowledge of the underlying fibrotic process is essential for the future development of novel therapies. There are many mediators and mechanisms of renal fibrosis reported in the literature, of which only a few have been investigated in the cat. This article reviews the process of renal fibrosis and discusses the most commonly cited mediators and mechanisms of progressive renal injury, with particular focus on the potential significance to feline CKD.
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Affiliation(s)
- Jack Lawson
- Comparative Biomedical Sciences, The Royal Veterinary College, Royal College Street, London NW1 0TU, UK.
| | - Jonathan Elliott
- Comparative Biomedical Sciences, The Royal Veterinary College, Royal College Street, London NW1 0TU, UK
| | - Caroline Wheeler-Jones
- Comparative Biomedical Sciences, The Royal Veterinary College, Royal College Street, London NW1 0TU, UK
| | - Harriet Syme
- Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire AL9 7TA, UK
| | - Rosanne Jepson
- Clinical Sciences and Services, The Royal Veterinary College, Hawkshead Lane, North Mymms, Hatfield, Hertfordshire AL9 7TA, UK
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Abstract
Cardinal pathological features of hypertensive heart disease (HHD) include not only hypertrophied cardiomyocytes and foci of scattered microscopic scarring, a footprint of prior necrosis, but also small myocytes ensnared by fibrillar collagen where disuse atrophy with protein degradation would be predicted. Whether atrophic signaling is concordant with the appearance of HHD and involves oxidative and endoplasmic reticulum (ER) stress remains unexplored. Herein, we examine these possibilities focusing on the left ventricle and cardiomyocytes harvested from hypertensive rats receiving 4 weeks aldosterone/salt treatment (ALDOST) alone or together with ZnSO₄, a nonvasoactive antioxidant, with the potential to attenuate atrophy and optimize hypertrophy. Compared with untreated age-/sex-/strain-matched controls, ALDOST was accompanied by (1) left ventricle hypertrophy with preserved systolic function; (2) concordant cardiomyocyte atrophy (<1000 μm²) found at sites bordering on fibrosis where they were reexpressing β-myosin heavy chain; and (3) upregulation of ubiquitin ligases, muscle RING-finger protein-1 and atrogin-1, and elevated 8-isoprostane and unfolded protein ER response with messenger RNA upregulation of stress markers. ZnSO₄ cotreatment reduced lipid peroxidation, fibrosis, and the number of atrophic myocytes, together with a further increase in cell area and width of atrophied and hypertrophied myocytes, and improved systolic function but did not attenuate elevated blood pressure. We conclude that atrophic signaling, concordant with hypertrophy, occurs in the presence of a reparative fibrosis and induction of oxidative and ER stress at sites of scarring where myocytes are atrophied. ZnSO₄ cotreatment in HHD with ALDOST attenuates the number of atrophic myocytes, optimizes size of atrophied and hypertrophied myocytes, and improves systolic function.
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Meng W, Zhao W, Zhao T, Liu C, Chen Y, Liu H, Sun Y. Autocrine and paracrine function of Angiotensin 1-7 in tissue repair during hypertension. Am J Hypertens 2014; 27:775-82. [PMID: 24429674 DOI: 10.1093/ajh/hpt270] [Citation(s) in RCA: 24] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND Angiotensin-converting enzyme 2 (ACE2) cleaves angiotensin (Ang) II to generate Ang1-7, which mediates cellular actions through Mas receptors (MasR). Hypertension is accompanied by high or low circulating AngII levels and cardiac/renal injury. The purpose of this study is to explore (i) whether circulating AngII affects ACE2/MasR expressions in the hypertensive heart and kidney; and (ii) whether Ang1-7 regulates cardiac repair/remodeling responses through MasR during hypertension. METHODS In the first portion of the study, rats received either an AngII infusion (400ng/kg/min) for 4 weeks, leading to hypertension with high circulating AngII, or an aldosterone (ALDO, 0.75 μg/h) infusion for 4 weeks, leading to hypertension with low/normal circulating AngII. Cardiac and renal ACE2/MasR expressions were examined. We found that cardiac ACE2 was increased and MasR attenuated in both AngII and ALDO groups. However, renal ACE2 and MasR remained unchanged in both AngII- and ALDO-treated animals. RESULTS In the second portion, rats received AngII infusion with/without MasR antagonist (A779, 1mg/kg/day) for 4 weeks. The roles of MasR blockade in cardiac inflammation, fibrosis, apoptosis, and ventricular function were examined. Chronic AngII infusion caused scattered cardiac injuries, and A779 cotreatment exacerbated cardiac injury, resulting in aggravated inflammatory, fibrogenic, and apoptotic responses compared with the AngII group. Cardiac function, however, was unaltered in the AngII and A779 groups. CONCLUSIONS ACE2 and MasR expressions in the hypertensive heart and kidney are not regulated by circulating AngII levels. Ang1-7 is involved in multiple repair responses, suggesting that therapeutic strategies aimed at administering Ang1-7 hold potential for the management of cardiac remodeling.
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Affiliation(s)
- Weixin Meng
- Division of Cardiac Surgery, Department of Surgery, First Affiliate Hospital of Harbin Medical University, Harbin, China
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Fogari R, Derosa G, Zoppi A, Lazzari P, D'Angelo A, Mugellini A. Comparative effect of canrenone or hydrochlorothiazide addition to valsartan/amlodipine combination on urinary albumin excretion in well-controlled type 2 diabetic hypertensive patients with microalbuminuria. Expert Opin Pharmacother 2014; 15:453-9. [DOI: 10.1517/14656566.2014.874415] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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Matsuki K, Hathaway CK, Lawrence MG, Smithies O, Kakoki M. The role of transforming growth factor β1 in the regulation of blood pressure. Curr Hypertens Rev 2014; 10:223-38. [PMID: 25801626 PMCID: PMC4842018 DOI: 10.2174/157340211004150319123313] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Revised: 02/19/2015] [Accepted: 02/23/2015] [Indexed: 01/21/2023]
Abstract
Although human association studies suggest a link between polymorphisms in the gene encoding transforming growth factor (TGF) β1 and differing blood pressure levels, a causative mechanism for this correlation remains elusive. Recently we have generated a series of mice with graded expression of TGFβ1, ranging from approximately 10% to 300% compared to normal. We have found that blood pressure and plasma volume are negatively regulated by TGFβ1. Of note, the 10% hypomorph exhibits primary aldosteronism and markedly impaired urinary excretion of water and electrolytes. We here review previous literature highlighting the importance of TGFβ signaling as a natriuretic system, which we postulate is a causative mechanism explaining how polymorphisms in TGFβ1 could influence blood pressure levels.
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Affiliation(s)
| | | | | | | | - Masao Kakoki
- Department of Pathology and Laboratory Medicine, University of North Carolina at Chapel Hill, CB #7525, 701 Brinkhous-Bullitt Building, Chapel Hill, NC 27599-7525, USA.
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Zou C, Xie R, Bao Y, Liu X, Sui M, M S, Li S, Yin H. Iron chelator alleviates tubulointerstitial fibrosis in diabetic nephropathy rats by inhibiting the expression of tenascinC and other correlation factors. Endocrine 2013; 44:666-74. [PMID: 23468095 DOI: 10.1007/s12020-013-9907-0] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/08/2012] [Accepted: 02/13/2013] [Indexed: 01/06/2023]
Abstract
Tubulointerstitial fibrosis is the final common pathway to diabetic nephropathy. However, only a few drugs are responsible for this pathologic process. We investigated the possible effect of deferiprone (iron chelator) treatment on experimental diabetic nephropathy (DN) rats, as well as the mechanisms involved in this process. Diabetic nephropathy was induced in rats by feeding on high-carbohydrate-fat food and injecting streptozotocin. After 20 weeks of deferiprone treatment, tubulointerstitial morphology was detected by staining with hematoxylin-eosin and Masson's trichrome. Tubulointerstitial fibrosis was measured using the point-counting technique. Biochemical parameters including fasting glucose, insulin resistance (IR), serum iron, ferritin, transferrin saturation (TS), and urinary albumin/creatinine ratio (UA/C) were detected in diabetic nephropathy models. Semiquantitative RT-PCR, western blot, and immunohistochemistry were utilized for evaluating mRNA and protein levels of tenascin C, fibronectin 1 (Fn1), TGF-β1, and collagen IV in nephridial tissue, respectively. Malonialdehyde (MDA) and superoxide dismutase (SOD) were determined by pyrogallol and thiobarbituric acid method. Tubulointerstitial fibrosis was significantly ameliorated after deferiprone treatment, and both mRNA and protein expressions of profibrotic factors were inhibited in treatment groups. Meanwhile, high levels of serum iron, ferritin, TS, and UA/C were observed in DN rats. These factors were down-regulated by deferiprone treatment. Furthermore, deferiprone effectively relieved serum IR and regulated oxidative stress process. Our results demonstrated the anti-fibrosis potential and renoprotective effects of deferiprone for diabetic nephropathy, and this process was partially mediated by tenascin C blocking.
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Affiliation(s)
- Chunbo Zou
- Department of Nephrology, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Str, Nangang District, Harbin, People's Republic of China
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Lan TH, Huang XQ, Tan HM. Vascular fibrosis in atherosclerosis. Cardiovasc Pathol 2013; 22:401-7. [DOI: 10.1016/j.carpath.2013.01.003] [Citation(s) in RCA: 122] [Impact Index Per Article: 10.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/19/2012] [Revised: 12/10/2012] [Accepted: 01/08/2013] [Indexed: 01/10/2023] Open
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Silveira KD, Barroso LC, Vieira AT, Cisalpino D, Lima CX, Bader M, Arantes RME, dos Santos RAS, Simões-e-Silva AC, Teixeira MM. Beneficial effects of the activation of the angiotensin-(1-7) MAS receptor in a murine model of adriamycin-induced nephropathy. PLoS One 2013; 8:e66082. [PMID: 23762470 PMCID: PMC3676359 DOI: 10.1371/journal.pone.0066082] [Citation(s) in RCA: 51] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/11/2012] [Accepted: 05/06/2013] [Indexed: 12/16/2022] Open
Abstract
Angiotensin-(1–7) [Ang-(1–7)] is a biologically active heptapeptide that may counterbalance the physiological actions of angiotensin II (Ang II) within the renin-angiotensin system (RAS). Here, we evaluated whether activation of the Mas receptor with the oral agonist, AVE 0991, would have renoprotective effects in a model of adriamycin (ADR)-induced nephropathy. We also evaluated whether the Mas receptor contributed for the protective effects of treatment with AT1 receptor blockers. ADR (10 mg/kg) induced significant renal injury and dysfunction that was maximal at day 14 after injection. Treatment with the Mas receptor agonist AVE 0991 improved renal function parameters, reduced urinary protein loss and attenuated histological changes. Renoprotection was associated with reduction in urinary levels of TGF-β. Similar renoprotection was observed after treatment with the AT1 receptor antagonist, Losartan. AT1 and Mas receptor mRNA levels dropped after ADR administration and treatment with losartan reestablished the expression of Mas receptor and increased the expression of ACE2. ADR-induced nephropathy was similar in wild type (Mas+/+) and Mas knockout (Mas−/−) mice, suggesting there was no endogenous role for Mas receptor activation. However, treatment with Losartan was able to reduce renal injury only in Mas+/+, but not in Mas−/− mice. Therefore, these findings suggest that exogenous activation of the Mas receptor protects from ADR-induced nephropathy and contributes to the beneficial effects of AT1 receptor blockade. Medications which target specifically the ACE2/Ang-(1–7)/Mas axis may offer new therapeutic opportunities to treat human nephropathies.
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Affiliation(s)
- Kátia Daniela Silveira
- Imunofarmacologia, Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Lívia Corrêa Barroso
- Imunofarmacologia, Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Angélica Thomáz Vieira
- Imunofarmacologia, Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Daniel Cisalpino
- Imunofarmacologia, Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Cristiano Xavier Lima
- Imunofarmacologia, Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- Departamento de Pediatria da Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | - Michael Bader
- Max Delbrück Center for Molecular Medicin, Berlin Buch, Germany
| | - Rosa Maria Esteves Arantes
- Departamento de Patologia Geral, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
| | | | - Ana Cristina Simões-e-Silva
- Departamento de Pediatria da Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- * E-mail: (ACSS); (MMT)
| | - Mauro Martins Teixeira
- Imunofarmacologia, Departamento de Bioquímica e Imunologia, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- Departamento de Pediatria da Faculdade de Medicina, Universidade Federal de Minas Gerais, Belo Horizonte, Minas Gerais, Brazil
- * E-mail: (ACSS); (MMT)
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Dong X, Geng Z, Zhao Y, Chen J, Cen Y. Involvement of mast cell chymase in burn wound healing in hamsters. Exp Ther Med 2012; 5:643-647. [PMID: 23408248 PMCID: PMC3570197 DOI: 10.3892/etm.2012.836] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2012] [Accepted: 11/19/2012] [Indexed: 01/23/2023] Open
Abstract
Mast cells play a significant role in the late stage of wound healing following burn injuries. In the present study, the possible role of mast cell chymase in burn wound healing was examined using a mast cell membrane stabilizer, ketotifen, in hamsters. A total of 28 hamsters were randomly divided into two groups (n=14), termed as the control and ketotifen groups. A deep partial-thickness burn injury was made on the back skin of the hamsters. The control group was orally administered physiological saline (1 ml) and the ketotifen group was orally administered ketotifen (4 mg/kg) once daily, two days prior to and two days subsequent to the burn. The results showed that concentrations of angiotensin II (Ang II), TGF-β1, collagens I and III and interleukin (IL)-1β were significantly decreased in the ketotifen group compared with those in the control group. However, there was no significant difference in fibroblast apoptosis between the two groups. The release of mast cell chymase was inhibited by the mast cell membrane stabilizer ketotifen. Taken together, these results suggest that mast cell chymase may participate in the process of burn wound healing. Chymase may therefore be a promising therapeutic target for the treatment of burn wounds.
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Affiliation(s)
- Xianglin Dong
- Department of Burns and Plastic Surgery, The First Affiliated Hospital of Xinjiang Medical University, Urumqi, Xinjiang Uigur Autonomous Region 830054
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Sipal S, Halici Z, Kiki I, Polat B, Albayrak A, Albayrak F, Karakus E, Aksak S, Ozturk B, Gundogdu C. Comparative study of three angiotensin II type 1 receptor antagonists in preventing liver fibrosis in diabetic rats: stereology, histopathology, and electron microscopy. J Mol Histol 2012; 43:723-35. [PMID: 22922994 DOI: 10.1007/s10735-012-9441-z] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2012] [Accepted: 08/11/2012] [Indexed: 01/12/2023]
Abstract
The presence of liver disease in patients with progressively worsening insulin resistance may not be recognized until patients develop manifestations of the metabolic syndrome such as diabetes, hypertension, hyperlipidemia, and vascular disease. It was aimed to investigate whether three angiotensin II type 1 receptor antagonists (ARBs) (olmesartan, losartan, and valsartan) had preventive effect against hepatic fibrosis and this was a common characteristic among ARBs. In current study, 25 adult male rats were used and divided into five groups: the non-diabetic healthy group, alloxan induced diabetic (AID) control group, AID losartan group, AID valsartan group and AID olmesartan group. According to numerical density of hepatocytes, significant difference was found between the non-diabetic healthy group and diabetic control group. All treatments groups were significant when compared to diabetic control group. In diabetic control group it was examined swelling, irregular cristae arrangement in some of mitochondria. It was also determined mitochondria membrane degeneration in some areas of section profiles. In diabetic rats treated with losartan group, there were necrotic hepatocytes. In diabetic rats treated with valsartan group, predominantly, findings were similar to losartan group. In diabetic rats treated with olmesertan group, plates of hepatocytes were quite regular. There were hardly necrotic cells. Not only other organelles such as RER, SER and lysosom but also mitochondrial structures had normal appearance. In the diabetic control group electron microscopy revealed edema in both the cytoplasm and perinuclear area and the nuclear membranes appeared damaged. In conclusion, it was established that the most protective ARB the liver in diabetic rats was olmesartan, followed by losartan.
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Affiliation(s)
- Sare Sipal
- Department of Pathology, Faculty of Medicine, Ataturk University, 25240, Erzurum, Turkey
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Blaes N, Pécher C, Mehrenberger M, Cellier E, Praddaude F, Chevalier J, Tack I, Couture R, Girolami JP. Bradykinin inhibits high glucose- and growth factor-induced collagen synthesis in mesangial cells through the B2-kinin receptor. Am J Physiol Renal Physiol 2012; 303:F293-303. [PMID: 22573379 DOI: 10.1152/ajprenal.00437.2011] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
Mesangial matrix expansion is an early lesion leading to glomeruloclerosis and chronic renal diseases. A beneficial effect is achieved with angiotensin I-converting enzyme inhibitors (ACEI), which also favor bradykinin (BK) B2 receptor (B2R) activation. To define the underlying mechanism, we hypothesized that B2R activation could be a negative regulator of collagen synthesis in mesangial cells (MC). We investigated the effect of BK on collagen synthesis and signaling in MC. Inflammation was evaluated by intercellular adhesion molecule-1 (ICAM-1) expression. BK inhibited collagen I and IV synthesis stimulated by high glucose, epithelial growth factor (EGF), and transforming growth factor-β (TGF-β) but did not alter ICAM-1. Inhibition of collagen synthesis was B2R but not B1R mediated. PKC or phosphatidylinositol 3-kinase (PI3K) inhibitors mimicked the BK effect. B2R activation inhibited TGF-β- and EGF-induced Erk1/2, Smad2/3, Akt S473, and EGFR phosphorylation. A phosphatase inhibitor prevented BK effects. The in vivo impact of B2R on mesangial matrix expansion was assessed in streptozotocin-diabetic rodents. Deletion of B2R increased mesangial matrix expansion and albuminuria in diabetic mice. In diabetic rats, matrix expansion and albuminuria were prevented by ACEI but not by ACEI and B2R antagonist cotreatment. Consistently, the lowered BK content of diabetic glomeruli was restored by ACEI. In conclusion, deficient B2R activation aggravated mesangial matrix expansion in diabetic rodents whereas B2R activation reduced MC collagen synthesis by a mechanism targeting Erk1/2 and Akt, common pathways activated by EGF and TGF-β. Taken together, the data support the hypothesis of an antifibrosing effect of B2R activation.
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Affiliation(s)
- Nelly Blaes
- INSERM U1048, Institut des Maladies Métaboliques et Cardiovasculaires (I2MC), Université Paul Sabatier, Toulouse Cedex. France
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Losartan reduces trinitrobenzene sulphonic acid-induced colorectal fibrosis in rats. CANADIAN JOURNAL OF GASTROENTEROLOGY = JOURNAL CANADIEN DE GASTROENTEROLOGIE 2012; 26:33-9. [PMID: 22288068 DOI: 10.1155/2012/628268] [Citation(s) in RCA: 35] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
BACKGROUND Intestinal fibrosis is a challenging clinical condition in several fibrostenosing enteropathies, particularly Crohn's disease. Currently, no effective preventive measures or medical therapies are available for intestinal fibrosis. Fibrosis, due to an abnormal accumulation of extracellular matrix proteins, is a chronic and progressive process mediated by cell⁄matrix⁄cytokine and growth factor interactions, but may be a reversible phenomenon. Of the several molecules regulating fibrogenesis, transforming growth factor-beta 1 (TGF-b1) appears to play a pivotal role; it is strongly induced by the local activation of angiotensin II. The levels of both TGF-b1 and angiotensin II are elevated in fibrostenosing Crohn's disease. AIMS To evaluate the in vivo effect of losartan - an angiotensin II receptor antagonist - on the course of chronic colitis-associated fibrosis and on TGF-b1 expression. METHODS Colitis was induced by intrarectal instillation of trinitrobenzene sulphonic acid (TNBS) (15 mg⁄mL) while losartan was administered orally daily by gavage (7 mg⁄kg⁄day) for 21 days. Three groups of rats were evaluated: control (n=10); TNBS treated (n=10); and TNBS + losartan treated (n=10). Inflammation and fibrosis of the colon were evaluated by macro- and microscopic score analysis. Colonic TGF-b1 levels was measured using ELISA. RESULTS Twenty-one days after induction, losartan significantly improved the macro- and microscopic scores of fibrosis in the colonic wall and reduced TGF-b1 concentration. CONCLUSIONS Prophylactic oral administration of losartan reduces the colorectal fibrosis complicating the TNBS-induced chronic colitis, an effect that appears to be mediated by a downregulation of TGF-b1 expression.
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