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Search Results: 1 - 10 of 114246 matches for " Peter W. Mathieson "
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Regulation of Neph3 gene in podocytes – key roles of transcription factors NF-κB and Sp1
Mervi Ristola, Satu Arpiainen, Moin A Saleem, Peter W Mathieson, Gavin I Welsh, Sanna Lehtonen, Harry Holth?fer
BMC Molecular Biology , 2009, DOI: 10.1186/1471-2199-10-83
Abstract: We cloned and characterized approximately 5 kb fragment upstream of the Neph3 gene. Neph3 proximal promoter near the transcription start site was found to be devoid of TATA and CAAT boxes, but to contain a highly GC-rich area. Using promoter reporter gene constructs, we localized the main activating regulatory region of Neph3 gene in its proximal promoter region from -105 to -57. Within this region, putative transcription factor binding sites for NF-κB and Sp1 were found by computational analysis. Mutational screening indicated that NF-κB and Sp1 response elements are essential for the basal transcriptional activity of the Neph3 promoter. Co-transfection studies further showed that NF-κB and Sp1 regulate Neph3 promoter activity. In addition, overexpression of NF-κB increased endogenous Neph3 gene expression. Chromatin immunoprecipitation assay using cultured human podocytes demonstrated that both NF-κB and Sp1 interact with the Neph3 promoter.Our results show that NF-κB and Sp1 are key regulators of Neph3 expression at the basal level in podocytes, therefore providing new insight into the molecular mechanisms that contribute to the expression of Neph3 gene.The glomerular filtration barrier consists of a fenestrated endothelium, a glomerular basement membrane and glomerular epithelial cells, podocytes. Podocytes surround the basement membrane of glomerular capillaries from the outside and present foot processes that are linked to each other with unique cell junction structures, the slit diaphragms (SD). According to the present view, SDs form the final barrier preventing leakage of plasma proteins from circulation to urine [1].Neph3, also known as filtrin, is a member of the Neph (nephrin-like proteins) family and shows sequence homology and structural similarity to two other Neph proteins, Neph1 and Neph2, and to nephrin [2-5]. All these are transmembrane proteins that belong to the immunoglobulin superfamily [3-5]. In podocytes, Neph3, like other Neph family protei
An In Vitro Model of the Glomerular Capillary Wall Using Electrospun Collagen Nanofibres in a Bioartificial Composite Basement Membrane
Sadie C. Slater, Vince Beachley, Thomas Hayes, Daming Zhang, Gavin I. Welsh, Moin A. Saleem, Peter W. Mathieson, Xuejun Wen, Bo Su, Simon C. Satchell
PLOS ONE , 2011, DOI: 10.1371/journal.pone.0020802
Abstract: The filtering unit of the kidney, the glomerulus, contains capillaries whose walls function as a biological sieve, the glomerular filtration barrier. This comprises layers of two specialised cells, glomerular endothelial cells (GEnC) and podocytes, separated by a basement membrane. Glomerular filtration barrier function, and dysfunction in disease, remains incompletely understood, partly due to difficulties in studying the relevant cell types in vitro. We have addressed this by generation of unique conditionally immortalised human GEnC and podocytes. However, because the glomerular filtration barrier functions as a whole, it is necessary to develop three dimensional co-culture models to maximise the benefit of the availability of these cells. Here we have developed the first two tri-layer models of the glomerular capillary wall. The first is based on tissue culture inserts and provides evidence of cell-cell interaction via soluble mediators. In the second model the synthetic support of the tissue culture insert is replaced with a novel composite bioartificial membrane. This consists of a nanofibre membrane containing collagen I, electrospun directly onto a micro-photoelectroformed fine nickel supporting mesh. GEnC and podocytes grew in monolayers on either side of the insert support or the novel membrane to form a tri-layer model recapitulating the human glomerular capillary in vitro. These models will advance the study of both the physiology of normal glomerular filtration and of its disruption in glomerular disease.
Mannose 6-Phosphate Receptor and Sortilin Mediated Endocytosis of α-Galactosidase A in Kidney Endothelial Cells
Thaneas Prabakaran, Rikke Nielsen, Simon C. Satchell, Peter W. Mathieson, Ulla Feldt-Rasmussen, S?ren S. S?rensen, Erik I. Christensen
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0039975
Abstract: Prominent vasculopathy in Fabry disease patients is caused by excessive intracellular accumulation of globotriaosylceramide (GL-3) throughout the vascular endothelial cells causing progressive cerebrovascular, cardiac and renal impairments. The vascular lesions lead to myocardial ischemia, atherogenesis, stroke, aneurysm, thrombosis, and nephropathy. Hence, injury to the endothelial cells in the kidney is a key mechanism in human glomerular disease and endothelial cell repair is an important therapeutic target. We investigated the mechanism of uptake of α-galactosidase A (α-Gal A) in renal endothelial cells, in order to clarify if the recombinant enzyme is targeted to the lysosomes via the universal mannose 6-phosphate receptor (M6PR) and possibly other receptors. Immunohistochemical localization of infused recombinant α-Gal A in a renal biopsy from a classic Fabry disease patient showed that recombinant protein localize in the endothelial cells of the kidney. Affinity purification studies using α-Gal A resins identified M6PR and sortilin as α-Gal A receptors in cultured glomerular endothelial cells. Immunohistochemical analyses of normal human kidney with anti-sortilin and anti-M6PR showed that sortilin and M6PR were expressed in the endothelium of smaller and larger vessels. Uptake studies in cultured glomerular endothelial cells of α-Gal A labeled with fluorescence and 125I showed by inhibition with RAP and M6P that sortilin and M6PR mediated uptake of α-Gal A. Biacore studies revealed that α-Gal A binds to human M6PR with very high affinity, but M6PR also binds to sortilin in a way that prevents α-Gal A binding to sortilin. Taken together, our data provide evidence that sortilin is a new α-Gal A receptor expressed in renal endothelial cells and that this receptor together with the M6PR is able to internalize circulating α-Gal A during enzyme replacement therapy in patients with Fabry disease.
IQGAP1 Interacts with Components of the Slit Diaphragm Complex in Podocytes and Is Involved in Podocyte Migration and Permeability In Vitro
Claire Rigothier, Patrick Auguste, Gavin I. Welsh, Sébastien Lepreux, Colette Deminière, Peter W. Mathieson, Moin A. Saleem, Jean Ripoche, Christian Combe
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0037695
Abstract: IQGAP1 is a scaffold protein that interacts with proteins of the cytoskeleton and the intercellular adhesion complex. In podocytes, IQGAP1 is associated with nephrin in the glomerular slit diaphragm (SD) complex, but its role remains ill-defined. In this work, we investigated the interaction of IQGAP1 with the cytoskeleton and SD proteins in podocytes in culture, and its role in podocyte migration and permeability. Expression, localization, and interactions between IQGAP1 and SD or cytoskeletal proteins were determined in cultured human podocytes by Western blot (WB), immunocytolocalization (IC), immunoprecipitation (IP), and In situ Proximity Ligation assay (IsPL). Involvement of IQGAP1 in migration and permeability was also assessed. IQGAP1 expression in normal kidney biopsies was studied by immunohistochemistry. IQGAP1 expression by podocytes increased during their in vitro differentiation. IC, IP, and IsPL experiments showed colocalizations and/or interactions between IQGAP1 and SD proteins (nephrin, MAGI-1, CD2AP, NCK 1/2, podocin), podocalyxin, and cytoskeletal proteins (α-actinin-4). IQGAP1 silencing decreased podocyte migration and increased the permeability of a podocyte layer. Immunohistochemistry on normal human kidney confirmed IQGAP1 expression in podocytes and distal tubular epithelial cells and also showed an expression in glomerular parietal epithelial cells. In summary, our results suggest that IQGAP1, through its interaction with components of SD and cytoskeletal proteins, is involved in podocyte barrier properties.
Reactive Oxygen Species Modulate the Barrier Function of the Human Glomerular Endothelial Glycocalyx
Anurag Singh, Raina D. Ramnath, Rebecca R. Foster, Emma C. Wylie, Vincent Fridén, Ishita Dasgupta, Borje Haraldsson, Gavin I. Welsh, Peter W. Mathieson, Simon C. Satchell
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0055852
Abstract: Reactive oxygen species (ROS) play a key role in the pathogenesis of proteinuria in glomerular diseases like diabetic nephropathy. Glomerular endothelial cell (GEnC) glycocalyx covers the luminal aspect of the glomerular capillary wall and makes an important contribution to the glomerular barrier. ROS are known to depolymerise glycosaminoglycan (GAG) chains of proteoglycans, which are crucial for the barrier function of GEnC glycocalyx. The aim of this study is to investigate the direct effects of ROS on the structure and function of GEnC glycocalyx using conditionally immortalised human GEnC. ROS were generated by exogenous hydrogen peroxide. Biosynthesis and cleavage of GAG chains was analyzed by radiolabelling (S35 and 3H-glucosamine). GAG chains were quantified on GEnC surface and in the cell supernatant using liquid chromatography and immunofluorescence techniques. Barrier properties were estimated by measuring trans-endothelial passage of albumin. ROS caused a significant loss of WGA lectin and heparan sulphate staining from the surface of GEnC. This lead to an increase in trans-endothelial albumin passage. The latter could be inhibited by catalase and superoxide dismutase. The effect of ROS on GEnC was not mediated via the GAG biosynthetic pathway. Quantification of radiolabelled GAG fractions in the supernatant confirmed that ROS directly caused shedding of HS GAG. This finding is clinically relevant and suggests a mechanism by which ROS may cause proteinuria in clinical conditions associated with high oxidative stress.
Morphine Induces Albuminuria by Compromising Podocyte Integrity
Xiqian Lan, Partab Rai, Nirupama Chandel, Kang Cheng, Rivka Lederman, Moin A. Saleem, Peter W. Mathieson, Mohammad Husain, John T. Crosson, Kalpna Gupta, Ashwani Malhotra, Pravin C. Singhal
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0055748
Abstract: Morphine has been reported to accelerate the progression of chronic kidney disease. However, whether morphine affects slit diaphragm (SD), the major constituent of glomerular filtration barrier, is still unclear. In the present study, we examined the effect of morphine on glomerular filtration barrier in general and podocyte integrity in particular. Mice were administered either normal saline or morphine for 72 h, then urine samples were collected and kidneys were subsequently isolated for immunohistochemical studies and Western blot. For in vitro studies, human podocytes were treated with morphine and then probed for the molecular markers of slit diaphragm. Morphine-receiving mice displayed a significant increase in albuminuria and showed effacement of podocyte foot processes. In both in vivo and in vitro studies, the expression of synaptopodin, a molecular marker for podocyte integrity, and the slit diaphragm constituting molecules (SDCM), such as nephrin, podocin, and CD2-associated protein (CD2AP), were decreased in morphine-treated podocytes. In vitro studies indicated that morphine modulated podocyte expression of SDCM through opiate mu (MOR) and kappa (KOR) receptors. Since morphine also enhanced podocyte oxidative stress, the latter seems to contribute to decreased SDCM expression. In addition, AKT, p38, and JNK pathways were involved in morphine-induced down regulation of SDCM in human podocytes. These findings demonstrate that morphine has the potential to alter the glomerular filtration barrier by compromising the integrity of podocytes.
Decreased CXCR1 and CXCR2 expression on neutrophils in anti-neutrophil cytoplasmic autoantibody-associated vasculitides potentially increases neutrophil adhesion and impairs migration
Nan Hu, Johanna Westra, Abraham Rutgers, Berber Doornbos-Van der Meer, Minke G Huitema, Coen A Stegeman, Wayel H Abdulahad, Simon C Satchell, Peter W Mathieson, Peter Heeringa, Cees G M Kallenberg
Arthritis Research & Therapy , 2011, DOI: 10.1186/ar3534
Abstract: Membrane expression of CXCR1/2 on neutrophils was assessed by flow cytometry. Serum levels of interleukin-8 (IL-8), tumor necrosis factor alpha (TNF-α), angiopoietin 1 and angiopoietin 2 from quiescent and active AAV patients and healthy controls (HC) were quantified by ELISA. Adhesion and transendothelial migration of isolated neutrophils were analyzed using adhesion assays and Transwell systems, respectively.Expression of CXCR1 and CXCR2 on neutrophils was significantly decreased in AAV patients compared to HC. Levels of IL-8, which, as TNFα, dose-dependently down-regulated CXCR1 and CXCR2 expression on neutrophils in vitro, were significantly increased in the serum of patients with active AAV and correlated negatively with CXCR1/CXCR2 expression on neutrophils, even in quiescent patients. Blocking CXCR1 and CXCR2 with repertaxin increased neutrophil adhesion and inhibited migration through a glomerular endothelial cell layer.Expression of CXCR1 and CXCR2 is decreased in AAV, potentially induced by circulating proinflammatory cytokines such as IL-8. Down-regulation of these chemokine receptors could increase neutrophil adhesion and impair its migration through the glomerular endothelium, contributing to neutrophil accumulation and, in concert with ANCA, persistent inflammation within the vessel wall.AAV comprises granulomatosis with polyangiitis (GPA), microscopic polyangiitis (MPA) and Churg Strauss syndrome (CSS), which share a spectrum of clinical manifestations reflecting necrotizing damage to small- and medium-sized vessels [1,2]. A role for neutrophils as effector cells in AAV is supported by a large body of evidence from in vitro and in vivo studies. After being primed by proinflammatory cytokines such as TNF-α, neutrophils can be activated by ANCA and release oxygen radicals and proteolytic enzymes, which have been shown to lyse endothelial cells in in vitro co-cultures [3,4]. In vivo, neutrophil accumulation in glomeruli has been observed in the early pha
A Proof Checking View of Parameterized Complexity
Luke Mathieson
Computer Science , 2012,
Abstract: The PCP Theorem is one of the most stunning results in computational complexity theory, a culmination of a series of results regarding proof checking it exposes some deep structure of computational problems. As a surprising side-effect, it also gives strong non-approximability results. In this paper we initiate the study of proof checking within the scope of Parameterized Complexity. In particular we adapt and extend the PCP[n log log n, n log log n] result of Feige et al. to several parameterized classes, and discuss some corollaries.
Graph Editing Problems with Extended Regularity Constraints
Luke Mathieson
Computer Science , 2015,
Abstract: Graph editing problems offer an interesting perspective on sub- and supergraph identification problems for a large variety of target properties. They have also attracted significant attention in recent years, particularly in the area of parameterized complexity as the problems have rich parameter ecologies. In this paper we examine generalisations of the notion of editing a graph to obtain a regular subgraph. In particular we extend the notion of regularity to include two variants of edge-regularity along with the unifying constraint of strong regularity. We present a number of results, with the central observation that these problems retain the general complexity profile of their regularity-based inspiration: when the number of edits $k$ and the maximum degree $r$ are taken together as a combined parameter, the problems are tractable (i.e. in \FPT{}), but are otherwise intractable. We also examine variants of the basic editing to obtain a regular subgraph problem from the perspective of parameterizing by the treewidth of the input graph. In this case the treewidth of the input graph essentially becomes a limiting parameter on the natural $k+r$ parameterization.
Demography and the Age of Rare Variants
Iain Mathieson ,Gil McVean
PLOS Genetics , 2014, DOI: doi/10.1371/journal.pgen.1004528
Abstract: Large whole-genome sequencing projects have provided access to much rare variation in human populations, which is highly informative about population structure and recent demography. Here, we show how the age of rare variants can be estimated from patterns of haplotype sharing and how these ages can be related to historical relationships between populations. We investigate the distribution of the age of variants occurring exactly twice ( variants) in a worldwide sample sequenced by the 1000 Genomes Project, revealing enormous variation across populations. The median age of haplotypes carrying variants is 50 to 160 generations across populations within Europe or Asia, and 170 to 320 generations within Africa. Haplotypes shared between continents are much older with median ages for haplotypes shared between Europe and Asia ranging from 320 to 670 generations. The distribution of the ages of haplotypes is informative about their demography, revealing recent bottlenecks, ancient splits, and more modern connections between populations. We see the effect of selection in the observation that functional variants are significantly younger than nonfunctional variants of the same frequency. This approach is relatively insensitive to mutation rate and complements other nonparametric methods for demographic inference.
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