Glomerular Endothelial Cell-Derived microRNA-192 Regulates Nephronectin Expression in Idiopathic Membranous Glomerulonephritis

2021 ◽  
Vol 32 (11) ◽  
pp. 2777-2794
Author(s):  
Janina Müller-Deile ◽  
Nina Sopel ◽  
Alexandra Ohs ◽  
Victoria Rose ◽  
Marwin Gröner ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Structural Changes ◽  
Membranous Glomerulonephritis ◽  
Glomerular Endothelial Cell ◽  
Filter Function ◽  
Content Type ◽  
Filtration Barrier ◽  
Advanced Stages ◽  
Complex Deposition ◽  
Idiopathic Membranous Glomerulonephritis

BackgroundAutoantibodies binding to podocyte antigens cause idiopathic membranous glomerulonephritis (iMGN). However, it remains elusive how autoantibodies reach the subepithelial space because the glomerular filtration barrier (GFB) is size selective and almost impermeable for antibodies.MethodsKidney biopsies from patients with iMGN, cell culture, zebrafish, and mouse models were used to investigate the role of nephronectin (NPNT) regulating microRNAs (miRs) for the GFB.ResultsGlomerular endothelial cell (GEC)-derived miR-192-5p and podocyte-derived miR-378a-3p are upregulated in urine and glomeruli of patients with iMGN, whereas glomerular NPNT is reduced. Overexpression of miR-192-5p and morpholino-mediated npnt knockdown induced edema, proteinuria, and podocyte effacement similar to podocyte-derived miR-378a-3p in zebrafish. Structural changes of the glomerular basement membrane (GBM) with increased lucidity, splitting, and lamellation, especially of the lamina rara interna, similar to ultrastructural findings seen in advanced stages of iMGN, were found. IgG-size nanoparticles accumulated in lucidity areas of the lamina rara interna and lamina densa of the GBM in npnt-knockdown zebrafish models. Loss of slit diaphragm proteins and severe structural impairment of the GBM were further confirmed in podocyte-specific Npnt knockout mice. GECs downregulate podocyte NPNT by transfer of miR-192-5p–containing exosomes in a paracrine manner.ConclusionsPodocyte NPNT is important for proper glomerular filter function and GBM structure and is regulated by GEC-derived miR-192-5p and podocyte-derived miR-378a-3p. We hypothesize that loss of NPNT in the GBM is an important part of the initial pathophysiology of iMGN and enables autoantigenicity of podocyte antigens and subepithelial immune complex deposition in iMGN.

scholarly journals FC 029PODOCYTE AND GLOMERULAR ENDOTHELIAL CELL DERIVED MICRORNAS REGULATE PODOCYTE NEPHRONECTIN IN MEMBRANOUS GLOMERULONEPHRITIS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Janina Müller-Deile ◽  
Nina Sopel ◽  
Alexandra Ohs ◽  
Ahmed Kotb ◽  
Groener Marwin ◽  
...  
Keyword(s):  
Endothelial Cell ◽  
Glomerular Filtration ◽  
Structural Changes ◽  
Membranous Glomerulonephritis ◽  
Glomerular Endothelial Cell ◽  
Glomerular Filtration Barrier ◽  
Filter Function ◽  
Filtration Barrier ◽  
Phospholipase A2 Receptor ◽  
Complex Deposition

Abstract Background and Aims Autoantibodies binding to podocyte antigens cause idiopathic membranous glomerulonephritis (iMGN). However, it remains elusive how autoantibodies reach the subepithelial space because the glomerular filtration barrier is normally size selective and impermeable for antibodies. Method Kidney biopsies from patients with MGN, cell culture, zebrafish and mice models were used to investigate the role of nephronectin (NPNT) regulating microRNAs (miRs) for the glomerular filtration barrier. Results We found that endothelial cell-derived miR-192-5p and podocyte-derived miR-378a-3p are upregulated in patients with anti-phospholipase A2 receptor antibody positive (PLA2R-ab+) iMGN and regulate glomerular NPNT expression (Fig. 1). Overexpression of miR-378a-3p and miR-192-5p as well as morpholino mediated npnt knockdown in zebrafish induced edema, proteinuria, loss of podocyte markers and podocyte effacement. The most prominent phenotype however were structural changes of the glomerular basement membrane (GBM) with increased lucidity, slicing and lamellation especially of the lamina rara interna (Fig. 2, Fig. 3). The phenotype was comparable to ultrastructural findings seen in iMGN. IgG sized nanoparticles accumulated in lucidity areas of the lamina rara interna and lamina densa of the GBM in npnt knockdown zebrafish models. Loss of slit diaphragm proteins and severe structural impairment of the GBM were further confirmed in podocyte specific Npnt knockout mice (Fig. 4). Conclusion Podocyte NPNT is important for proper glomerular filter function and GBM structure and is regulated by podocyte and glomerular endothelial cell derived miRs. We hypothesize that loss of NPNT in the GBM is part of the pathophysiology of iMGN and enables subepithelial immune complex deposition in iMGN.

scholarly journals Glomerular endothelial cell fenestrations: an integral component of the glomerular filtration barrier

2009 ◽  
Vol 296 (5) ◽  
pp. F947-F956 ◽  
Author(s):  
Simon C. Satchell ◽  
Filip Braet
Keyword(s):  
Endothelial Cell ◽  
Glomerular Filtration ◽  
In Vitro Models ◽  
Glomerular Injury ◽  
Glomerular Endothelial Cell ◽  
Glomerular Filtration Barrier ◽  
Therapeutic Implications ◽  
Filtration Barrier ◽  
Glomerular Development

Glomerular endothelial cell (GEnC) fenestrations are analogous to podocyte filtration slits, but their important contribution to the glomerular filtration barrier has not received corresponding attention. GEnC fenestrations are transcytoplasmic holes, specialized for their unique role as a prerequisite for filtration across the glomerular capillary wall. Glomerular filtration rate is dependent on the fractional area of the fenestrations and, through the glycocalyx they contain, GEnC fenestrations are important in restriction of protein passage. Hence, dysregulation of GEnC fenestrations may be associated with both renal failure and proteinuria, and the pathophysiological importance of GEnC fenestrations is well characterized in conditions such as preeclampsia. Recent evidence suggests a wider significance in repair of glomerular injury and in common, yet serious, conditions, including diabetic nephropathy. Study of endothelial cell fenestrations is challenging because of limited availability of suitable in vitro models and by the requirement for electron microscopy to image these sub-100-nm structures. However, extensive evidence, from glomerular development in rodents to in vitro studies in human GEnC, points to vascular endothelial growth factor (VEGF) as a key inducer of fenestrations. In systemic endothelial fenestrations, the intracellular pathways through which VEGF acts to induce fenestrations include a key role for the fenestral diaphragm protein plasmalemmal vesicle-associated protein-1 (PV-1). The role of PV-1 in GEnC is less clear, not least because of controversy over existence of GEnC fenestral diaphragms. In this article, the structure-function relationships of GEnC fenestrations will be evaluated in depth, their role in health and disease explored, and the outlook for future study and therapeutic implications of these peculiar structures will be approached.

scholarly journals Glomerular endothelial cell IQGAP2 and filtration barrier function

2016 ◽  
Vol 89 (5) ◽  
pp. 1160-1161 ◽  
Author(s):  
Fengyun Dong ◽  
Liqun Li ◽  
Xiaocui Chen ◽  
Thaddeus Allen ◽  
Ju Liu
Keyword(s):  
Endothelial Cell ◽  
Barrier Function ◽  
Glomerular Endothelial Cell ◽  
Filtration Barrier

What's happening to international business?

2014 ◽  
Vol 10 (1/2) ◽  
pp. 51-64 ◽  
Author(s):  
Snejina Michailova ◽  
Janne Tienari
Keyword(s):  
International Business ◽  
Design Methodology ◽  
Structural Changes ◽  
Business Schools ◽  
Academic Discipline ◽  
Academic Community ◽  
Content Type ◽  
Disciplinary Identity ◽  
Management Scholar ◽  
Self Examination

Purpose – This paper aims to outline different views on international business (IB) as an academic discipline and looks into how IB scholars can cope with challenges to their disciplinary identity when stand-alone IB departments are merged with other departments such as management, marketing or strategy in business schools and universities. Design/methodology/approach – The article offers a critical reflection on the development and future of IB as a discipline. The two authors are an IB and a Management scholar, both of whom were engaged in recent departmental mergers at their respective business schools. While the authors do not analyze these particular mergers, their experiences are inevitably interwoven in the views they express. Findings – Mergers of stand-alone IB departments with other departments bring to light the nature of the IB discipline as a contested terrain. The article discusses how these structural changes challenge the disciplinary identity of IB scholars. It contributes, first, to discussions on the development of IB as a discipline and, second, to understanding identities and identification during major organizational change events in academia. Research limitations/implications – The authors suggest that the threat of marginalization of IB in the context of business schools and universities necessitates a move beyond the “big questions” debate to a critical self-examination and reflection on IB as a discipline and as a global scholarly community. Originality/value – The article offers a critical view on current processes and challenges related to IB as a discipline and an academic community.

scholarly journals Antimicrobial Properties of 8-Hydroxyserrulat-14-en-19-oic Acid for Treatment of Implant-Associated Infections

2012 ◽  
Vol 57 (1) ◽  
pp. 333-342 ◽  
Author(s):  
Justyna Nowakowska ◽  
Hans J. Griesser ◽  
Marcus Textor ◽  
Regine Landmann ◽  
Nina Khanna
Keyword(s):  
Structural Changes ◽  
Treatment Options ◽  
Antimicrobial Properties ◽  
Bactericidal Effect ◽  
Mouse Tissue ◽  
Logarithmic Phase ◽  
Content Type ◽  
Gram Positive Bacteria ◽  
Time Kill

ABSTRACTTreatment options are limited for implant-associated infections (IAI) that are mainly caused by biofilm-forming staphylococci. We report here on the activity of the serrulatane compound 8-hydroxyserrulat-14-en-19-oic acid (EN4), a diterpene isolated from the Australian plantEremophila neglecta. EN4 elicited antimicrobial activity toward various Gram-positive bacteria but not to Gram-negative bacteria. It showed a similar bactericidal effect against logarithmic-phase, stationary-phase, and adherentStaphylococcus epidermidis, as well as against methicillin-susceptible and methicillin-resistantS. aureuswith MICs of 25 to 50 μg/ml and MBCs of 50 to 100 μg/ml. The bactericidal activity of EN4 was similar againstS. epidermidisand its Δicamutant, which is unable to produce polysaccharide intercellular adhesin-mediated biofilm. In time-kill studies, EN4 exhibited a rapid and concentration-dependent killing of staphylococci, reducing bacterial counts by >3 log10CFU/ml within 5 min at concentrations of >50 μg/ml. Investigation of the mode of action of EN4 revealed membranolytic properties and a general inhibition of macromolecular biosynthesis, suggesting a multitarget activity.In vitro-tested cytotoxicity on eukaryotic cells was time and concentration dependent in the range of the MBCs. EN4 was then tested in a mouse tissue cage model, where it showed neither bactericidal nor cytotoxic effects, indicating an inhibition of its activity. Inhibition assays revealed that this was caused by interactions with albumin. Overall, these findings suggest that, upon structural changes, EN4 might be a promising pharmacophore for the development of new antimicrobials to treat IAI.

Driving forces and structural changes of China as a market provider for Korea

2018 ◽  
Vol 22 (3) ◽  
pp. 194-211 ◽  
Author(s):  
Yongqi Feng ◽  
Tianshu Zhang
Keyword(s):  
Steady State ◽  
Driving Force ◽  
Design Methodology ◽  
Structural Changes ◽  
Driving Forces ◽  
Consumption Expenditure ◽  
Input Output ◽  
Content Type ◽  
Fixed Capital Formation ◽  
The Impact

Purpose The purpose of this paper is to provide a better understanding of the driving forces and structural changes of China as a market provider for Korea. This paper gives the answers for the following questions: How do China’s final demands trigger the growth of its imports from Korea? And what’s the impact of China’s final demands on the import in different industries? Design/methodology/approach Based on the Multi-Regional Input-Output model and World Input-Output Table database, this paper constructs the non-competitive imports input-output (IO) table of China to Korea. According to this table, we can calculate the induced imports coefficient and comprehensive induced import coefficients of China’s four final demands for imports from Korea in the 56 industries in China. Findings Among the four driving forces, the strongest one is changes in inventories and valuables. The impact of final consumption expenditure and fixed capital formation is much lower than that of changes in inventories and valuables, but they have a broader impact for the 56 industries. This paper finds out the China’s import induction of the final demands to Korea peaked in 2005 and 2010 and decreased greatly in 2014, so the position of China as market provider for Korea will no longer rise substantially, contrarily it will be in a steady state. Originality/value First, this paper constructs the non-competitive IO table to analyze the market provider issues between two countries and provides practical ways and methods for studies on the issues of imports and market provider. Second, this paper investigates the different roles of four final demands on driving force of China as market provider for Korea and the structural changes of China as a market provider for Korea among 56 industries from 2000 to 2014.

Transnationality in the XXI century. Concept and indicators

2021 ◽  
Vol ahead-of-print (ahead-of-print) ◽  
Author(s):  
Grazia Ietto-Gillies
Keyword(s):  
Structural Changes ◽  
Transnational Corporation ◽  
First Century ◽  
Future Research ◽  
Content Type ◽  
Low Degree ◽  
Fixed Assets ◽  
Inclusive Concept ◽  
The Impact

Purpose The purpose of this paper is to analyse the impact of major structural changes on the conceptualization of the transnational corporation (TNC) based on foreign direct investment (FDI) and on indicators of transnationality. Design/methodology/approach Analysis of three major structural changes which impact the current conception of transnationality. They are: the rise of digital companies; the increased role of finance in the economy; externalization of activities via non-equity modalities (NEMs) with an impact on FDI and on the labour market. Findings The paper finds that the current concept of transnationality needs widening to take account of companies with a low degree of fixed assets abroad such as the digital and the financial companies and those internationalizing via NEMs, as well as to take account of the evolving relationship between TNCs and labour. Research limitations/implications Future research along the lines proposed should consider: working explicitly with the new, inclusive concept of transnationality and arrive at an empirical estimate of the proposed indices of transnationality which modify and amplify the current United Nations Conference on Trade and Development indices. Social implications Useful for understanding the nature of transnationality in the twenty-first century and for developing policies. Originality/value The paper proposes a new concept of transnationality and of the TNC, one that allows for new ways of organizing direct business activities abroad. It also proposes broadening the list of indicators of transnationality.

Servitisation through structural adaptation

2021 ◽  
Vol 31 (3) ◽  
pp. 468-490
Author(s):  
Saad Zighan ◽  
Ziad Alkalha ◽  
David Bamford ◽  
Iain Reid ◽  
Zu'bi M.F. Al-Zu'bi
Keyword(s):  
Service Provision ◽  
Design Theory ◽  
Structural Changes ◽  
Oil And Gas ◽  
Project Managers ◽  
The Body ◽  
Exploratory Research ◽  
Organisational Structure ◽  
Structural Adaptation ◽  
Content Type

PurposeThe purpose of this study is to investigate the structural changes needed for project-based organisations (PBOs) to synthesise their project operations and services following the servitisation strategy. It addresses the question of how PBOs should change their organisational structure fitting with service provision strategy.Design/methodology/approachThis study followed an exploratory research method using a single in-depth case with evidence collected from 51 project managers from five different industry sectors: construction, oil and gas, IT, logistics and health careFindingsCapitalising on organisational design theory, it has been found that successfully extending PBOs' outcomes into a system of both project output and extra services requires an adjustment of organisational structure that creates greater value for both companies and customers. This required adjustment has been divided into five main categories: (1) collaboration cross-project and customers; (2) flexible workflow, (3) decentralised decision-making, (4) wide span of control and (5) project governance. However, the findings indicate that success can only be ensured by particular mutually coordinated organisational designs with a suitable balance of products and servicesPractical implicationsThis study presents vital indicators to PBOs practitioners when deploying servitisation within their operational strategy by adjusting the organisation's design.Social implicationsServitisation could add both economic and social values for a diverse set of project stakeholders. However, the sustainability performance of servitisation in servitised project-based organisations is an outcome of reducing the discrepancy between project operation and service provision activities.Originality/valueThis study contributes to the body of knowledge and proposes a structural alteration process in PBOs to help align project operations and service provision activities. It explains how project-based organisations reconfigure their resources to provide services.

scholarly journals Needs of patient with advanced stages of cancer in a Thai community

2018 ◽  
Vol 32 (5) ◽  
pp. 342-351
Author(s):  
Panita Krongyuth ◽  
Pimpan Silpasuwan ◽  
Chukiat Viwatwongkasem ◽  
Cathy Campbell
Keyword(s):  
Palliative Care ◽  
Content Analysis ◽  
Pain Management ◽  
Care Providers ◽  
Care Needs ◽  
Open Communication ◽  
Content Type ◽  
Advanced Stages ◽  
Palliative Care Needs ◽  
At Home

Purpose The purpose of this paper is to explore the needs of people with cancer in advanced stages and to analyze factors that influence them. Design/methodology/approach A concurrent mixed-method design was used. Descriptive design was conducted in Ubon Ratchathani Province, Thailand. Data were collected from a convenience sample of patients with advanced cancer of any tissue or organ. Questionnaires were completed by 110 patients aged 60 years and above (response rate 110/130=84.6 percent). In-depth interviews were conducted with a total of eight patients. Content analysis of semi-structured interviews of a sub-sample was subsequently performed to better understand the real needs of patients with advanced stages of cancer at home setting. Findings The majority (77.5 percent) reported a preference to spend their final days at home. The four most common palliative care needs were more information about disease and medical treatment (98.2 percent), more treatment for pain (97.3 percent), health education for family caregivers (95.5 percent) and health volunteers visit at home (95.5 percent). Content analysis of the qualitative data suggested that patient needs health care providers to deliver open communication, pain management and provide psychosocial supports. Originality/value The result showed that patients-related variables are associated with the palliative care needs in patients with advanced stages of cancer. Communication skills and pain management are the key components to support the need for palliative care at home and to benefit the quality of life in terminally ill patients.

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