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An investigation of the role of the P2X7 purinoceptor in the pathogenesis of diabetic nephropathy
Get PDFP2X7 is a member of the P2X purinoceptor family and functions as an ATP-gated non-selective cation channel. Expression is greatest in cells of the immune system where it plays a key role in the orchestration of IL1β maturation and release. Diabetic nephropathy (DN) is traditionally considered a ‘metabolic’ disease, but is increasingly recognized to have an important inflammatory component. The work in this thesis tests the hypothesis that P2X7 contributes to the pathogenesis of DN and, in particular, development of renal inflammation in this disease. P2X7 expression was examined by immunohistochemistry in human kidney biopsy tissue; glomerular expression was identified in a subset of patients with early clinical DN. P2X7 expression was also upregulated at 12 weeks in glomeruli of rodents with both type 1 and type 2 diabetes. After induction of diabetes with low-dose STZ, GSK P2X7 KO mice exhibited a marked reduction in glomerular macrophage infiltration compared to WT, without impact on albuminuria or serum creatinine. A trend towards protection against induction of diabetes was also apparent in GSK KO mice; this protection was more pronounced in the Pfizer P2X7 KO strain and accompanied by reduced islet macrophage infiltration and preservation of β-cell mass. The mechanism linking P2X7 and glomerular macrophage infiltration was explored in vitro. A selective P2X7 antagonist, A438079, partially abrogated hyperglycaemia-induced secretion of the macrophage chemokine, MCP-1, from primary human mesangial cells (pHMC). MCP-1 secretion was enhanced by the ATP-hydrolysing agent, apyrase, as well as by application of 5-BDBD, a selective P2X4 antagonist, suggesting chemokine secretion from pHMCs may be modulated by competing purinoceptor signals. In summary, P2X7 is upregulated at an early time-point in rodent diabetic glomeruli, and contributes to glomerular and pancreatic inflammation in murine experimental disease. Comparable upregulation of P2X7 observed in human glomeruli in DN bodes well for future translational studies
Inhibition of the purinergic P2X7 receptor improves renal perfusion in angiotensin-II-infused rats.
No full textChronic activation of the renin–angiotensin system promotes hypertension, renal microvascular dysfunction, tissue hypoxia, and inflammation. Despite similar hypertension, an injurious response to excess angiotensin II is greater in F344 than in Lewis rats; the latter displaying renoprotection. Here we studied whether p2rx7, encoding the P2X7 receptor (P2X7R), is a candidate gene for the differential susceptibility to vascular dysfunction under high angiotensin II tone. A 14-day infusion of angiotensin II into F344 rats increased blood pressure by about 15 mm Hg without inducing fibrosis or albuminuria. In vivo pressure natriuresis was suppressed, medullary perfusion reduced by half, and the corticomedullary oxygenation gradient disrupted. Selective P2X7R antagonism restored pressure natriuresis, promoting a significant leftward shift in the intercept and increasing the slope. Sodium excretion was increased sixfold and blood pressure normalized. The specific P2X7R antagonist AZ11657312 increased renal medullary perfusion, but only in angiotensin II–treated rats. Tissue oxygenation was improved by P2X7R blockade, particularly in poorly oxygenated regions of the kidney. Thus, activation of P2X7R induces microvascular dysfunction and regional hypoxia when angiotensin II is elevated and these effects may contribute to progression of renal injury induced by chronic angiotensin II
Going Beyond Counting First Authors in Author Co-citation Analysis
Get PDFThe present study examines one of the fundamental aspects of author co-citation analysis (ACA) - the way co-citation
counts are defined. Co-citation counting provides the data on which all subsequent statistical analyses and mappings
are based, and we compare ACA results based on two different types of co-citation counting - the traditional type that
only counts the first one among a cited work's authors on the one hand and a non-traditional type that takes into
account the first 5 authors of a cited work on the other hand. Results indicate that the picture produced through this non-traditional author co-citation counting contains more coherent author groups and is therefore considerably clearer. However, this picture represents fewer specialties in the research field being studied than that produced through the traditional first-author co-citation counting when the same number of top-ranked authors is selected and analyzed. Reasons for these effects are discussed
Variations on the Author
Get PDF“Variations on the Author” discusses two of Eduardo Coutinho’s recent films (Um Dia na Vida, from 2010, and Últimas Conversas, posthumously released in 2015) and their contribution to the general question of documentary authorship. The director’s filmography is characterized by a consistent yet self-effacing form of authorial self-inscription: Coutinho often features as an interviewer that rather than express opinions propels discourses; an interviewer that is good at listening. This mode of self-inscription characterizes him as an author who is not expressive but who is nonetheless markedly present on the screen. In Um Dia na Vida, however, Coutinho is completely absent form the image, while Últimas Conversas, on the contrary, includes a confessional prologue that moves the director from the margins to the center of his films. This article examines the ways in which these works stand out in the filmography of a director who offers new insights into the notion of cinematic authorship
Appropriate Similarity Measures for Author Cocitation Analysis
Get PDFWe provide a number of new insights into the methodological discussion about author cocitation analysis. We first argue that the use of the Pearson correlation for measuring the similarity between authors’ cocitation profiles is not very satisfactory. We then discuss what kind of similarity measures may be used as an alternative to the Pearson correlation. We consider three similarity measures in particular. One is the well-known cosine. The other two similarity measures have not been used before in the bibliometric literature. Finally, we show by means of an example that our findings have a high practical relevance.information science;Pearson correlation;cosine;similarity measure;author cocitation analysis
A study of the P2X7 purinoceptor and vascular ATP metabolic pathways in chronic kidney disease-associated arterial calcification
Get PDFThe risk of cardiovascular-related death is several-fold higher in patients with chronic kidney disease (CKD) compared with the general population. Arterial calcification (AC) is extremely common in patients with CKD and strongly associates with cardiovascular-related mortality, however, there are currently no specific treatments to prevent its development and/or progression. Abundant evidence now suggests that AC is cell-mediated and actively-regulated, involving mechanisms linked to bone homeostasis, production of calcification inhibitors and vascular smooth muscle cell (VSMC) function. The P2X7 receptor (P2X7R) is an ATP-sensitive cation channel which has been implicated in several biological processes, in non-vascular contexts, thought to be important in the aetiology of AC. In addition, disruption to the normal function of some enzymes involved in ATP metabolism has been shown to contribute to AC, although little is known about their role in CKD-related arterial calcium deposition. The work in this thesis tested the primary hypothesis that P2X7R contributes to the pathogenesis of CKD-associated AC. Preliminary work was also conducted to examine the expression of components of the ATP-metabolising system in this clinical setting. P2X7R expression was confirmed in human and rodent vascular smooth muscle but was un-affected by calcification. In vitro, the P2X7R-specific antagonist, A438079, did not influence calcium deposition occurring in the presence of human VSMCs or segments of rat aorta exposed to ‘calcification-promoting’ medium. Calcification of cultured rat aorta was also not influenced by a second P2X7R-specific antagonist, A839977, or by BzATP (a receptor agonist). Aortic rings from mice deficient in P2X7R calcified to a similar extent to wild-type controls in vitro. A novel, adenine-based mouse model was developed to evaluate the effect of P2X7R gene deficiency on CKD-associated AC in vivo. However, the number of mice exhibiting AC in the final experiment was too low to draw any firm conclusion. Therefore, rats were fed an adenine-containing, high phosphate diet for 4 weeks (to induce CKD and AC) and administered a selective P2X7R antagonist, twice daily, throughout this period. Pharmacological blockade of P2X7R did not influence the magnitude of aortic calcification in this model. Quantification of mRNA performed on tissue obtained from the in vivo rat experiment suggested that VSMC-specific markers are down-regulated in calcified arteries, although VSMC osteogenic transformation, which is widely reported in the literature to occur in the context of AC, was not detected. Expression of the apoptosis marker, caspase-3, was increased in calcified arteries in vivo. P2X7R blockade did not influence any of these changes in mRNA expression. Expression of mRNA for ENPP-1, an ATP-metabolising enzyme responsible for the generation of the calcification inhibitor, pyrophosphate (PPi), was significantly increased in calcified arteries from CKD rats. Functional activity of ENPP-1 was also increased in these vessels. The expression of mRNA for other components of the ATP-metabolising system was also in keeping with an attempt by VSMCs to generate more PPi, possibly as an adaptive, defensive response to uraemic, calcification-promoting factors. Furthermore, an increase in ENPP-1 mRNA expression was detected in calcified inferior epigastric arteries from patients with end-stage renal disease (extracted at the time of kidney transplantation). In summary, P2X7R does not appear to contribute to the pathogenesis of CKD-associated AC, although this should be confirmed in experimental models which more closely simulate human disease. Arterial expression of enzymes involved in the metabolism of ATP does seem to change in AC. Future work should therefore focus on gauging the clinical relevance of this in order to better understand the mechanisms underlying the disease and potentially develop new therapeutic interventions
The role of the spleen tyrosine kinase pathway in driving inflammation in IgA nephropathy
No full textIgA nephropathy is the most common type of primary glomerulonephritis worldwide. At least 25% of patients may progress to kidney failure requiring dialysis or transplantation. Treatment of IgA nephropathy using generalised immunosuppression is controversial, with concerns regarding the balance of safety and efficacy in a non-specific approach. The aim of this review is to describe the recent scientific evidence, and a current clinical trial, investigating whether spleen tyrosine kinase (SYK) may be a novel and selective therapeutic target for IgA nephropathy. SYK, a cytoplasmic tyrosine kinase, has a pivotal role as an early intermediate in intracellular signal transduction cascades for the B cell receptor and the immunoglobulin Fc receptor, and thus is critical for B cell proliferation, differentiation and activation, and for mediating pro-inflammatory responses following Fc receptor engagement in various cell types. In renal biopsies of patients with IgA nephropathy, increased expression and phosphorylation of SYK were detected, and this correlated with the histological features of mesangial and endocapillary proliferation. In cell culture studies, patient-derived IgA1 stimulated mesangial cell SYK activation, cell proliferation and cytokine production, and these responses were attenuated by pharmacological or molecular inhibition of SYK. A global randomised, double-blind, placebo-controlled trial investigating the safety and efficacy of fostamatinib (an oral pro-drug SYK inhibitor) in the treatment of patients with IgA nephropathy is ongoing, which may provide important evidence of the safety and efficacy of targeting this pathway in clinical disease
Dispelling the Myths Behind First-author Citation Counts
Get PDFWe conducted a full-scale evaluative citation analysis study of scholars in the XML research field to explore just how different from each other author rankings resulting from different citation counting methods actually are, and to demonstrate the capability of emerging data and tools on the Web in supporting more realistic citation counting methods. Our results contest some common arguments for the continued
use of first-author citation counts in the evaluation of scholars, such as high correlations between author rankings by first-author citation counts and other citation
counting methods, and high costs of using more realistic citation counting methods that are not well-supported by the ISI databases. It is argued that increasingly available digital full text research papers make it possible for citation analysis studies to go beyond what the ISI databases have directly supported and to employ more
sophisticated methods
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