Publications
149 results found
McAdoo SP, Tanna A, McDaid J, et al., 2014, SYK inhibition in experimental autoimmune vasculitis and its glomerular expression in ANCA-associated vasculitis, LANCET, Vol: 383, Pages: 72-72, ISSN: 0140-6736
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- Citations: 3
Kim MJ, Turner CM, Hewitt R, et al., 2014, Exaggerated renal fibrosis in P2X4 receptor-deficient mice following unilateral ureteric obstruction, Nephrology Dialysis Transplantation, Vol: 29, Pages: 1350-1361, ISSN: 1460-2385
Background. The ATP-sensitive P2X7 receptor (P2X7R) hasbeen shown to contribute to renal injury in nephrotoxic nephritis,a rodent model of acute glomerulonephritis, and in unilateral uretericobstruction (UUO), a rodent model of chronic interstitialinflammation and fibrosis. Renal tubular cells, endothelial cellsand macrophages also express the closely related P2X4 receptor(P2X4R), which is chromosomally co-located with P2X7R andhas 40% homology; it is also pro-inflammatory and has beenshown to interact with P2X7R to modulate its pro-apoptotic andpro-inflammatory effects. Therefore, we chose to explore the functionof P2X4R in the UUO model of renal injury using knockoutmice. We hypothesized that UUO-induced tubulointerstitialdamage and fibrosis would also be attenuated in P2X4R−/− mice.Method. P2X4R−/− and wild-type (WT) mice were subjectedto either UUO or sham operation. Kidney samples taken onDays 7 and 14 were evaluated for renal inflammation and fi-brosis, and expression of pro-fibrotic factors.Results. To our surprise, the obstructed kidney in P2X4R−/−mice showed more severe renal injury, more collagen deposition( picrosirius red staining, increase of 53%; P < 0.05) andmore type I collagen staining (increase of 107%; P < 0.01), aswell as increased mRNA for TGF-β (increase of 102%, P <0.0005) and CTGF (increase of 157%; P < 0.05) by Day 14,compared with the UUO WT mice.Conclusion. These findings showed that lack of P2X4Rexpression leads to increased renal fibrosis, and increasedexpression of TGF-β and CTGF in the UUO model.
Turner CM, Arulkumaran N, Singer M, et al., 2014, Is the inflammasome a potential therapeutic target in renal disease?, BMC Nephrology, Vol: 15, ISSN: 1471-2369
The inflammasome is a large, multiprotein complex that drives proinflammatory cytokine production in response toinfection and tissue injury. Pattern recognition receptors that are either membrane bound or cytoplasmic triggerinflammasome assembly. These receptors sense danger signals including damage-associated molecular patterns andpathogen-associated molecular patterns (DAMPS and PAMPS respectively). The best-characterized inflammasome is theNLRP3 inflammasome. On assembly of the NLRP3 inflammasome, post-translational processing and secretion ofpro-inflammatory cytokines IL-1β and IL-18 occurs; in addition, cell death may be mediated via caspase-1. Intrinsic renalcells express components of the inflammasome pathway. This is most prominent in tubular epithelial cells and, to alesser degree, in glomeruli. Several primary renal diseases and systemic diseases affecting the kidney are associated withNLRP3 inflammasome/IL-1β/IL-18 axis activation. Most of the disorders studied have been acute inflammatory diseases.The disease spectrum includes ureteric obstruction, ischaemia reperfusion injury, glomerulonephritis, sepsis, hypoxia,glycerol-induced renal failure, and crystal nephropathy. In addition to mediating renal disease, the IL-1/ IL-18 axis mayalso be responsible for development of CKD itself and its related complications, including vascular calcification andsepsis. Experimental models using genetic deletions and/or receptor antagonists/antiserum against the NLRP3inflammasome pathway have shown decreased severity of disease. As such, the inflammasome is an attractivepotential therapeutic target in a variety of renal diseases.
Tanna A, Tam FWK, Pusey CD, 2013, B-cell-targeted therapy in adult glomerulonephritis, EXPERT OPINION ON BIOLOGICAL THERAPY, Vol: 13, Pages: 1691-1706, ISSN: 1471-2598
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- Citations: 8
Neff KJ, Frankel AH, Tam FWK, et al., 2013, The effect of bariatric surgery on renal function and disease: a focus on outcomes and inflammation, NEPHROLOGY DIALYSIS TRANSPLANTATION, Vol: 28, Pages: 73-82, ISSN: 0931-0509
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- Citations: 32
Arulkumaran N, Sixma ML, Saeed S, et al., 2013, RENAL MACROPHAGE INFILTRATION IN A RAT MODEL OF SEPSIS AND RECOVERY, ESICM 26th Annual Congress, Publisher: SPRINGER, Pages: S459-S460, ISSN: 0342-4642
Arulkumaran N, Sixma ML, Bass P, et al., 2013, TEMPORAL CHANGES IN RENAL HAEMODYNAMICS AND OXYGENATION IN A RAT MODEL OF SEPSIS, ESICM 26th Annual Congress, Publisher: SPRINGER, Pages: S459-S459, ISSN: 0342-4642
Arulkumaran N, Turner CM, Sixma ML, et al., 2013, Purinergic signaling in inflammatory renal disease, Frontiers in Physiology, Vol: 4, ISSN: 1664-042X
Extracellular purines have a role in renal physiology and adaption to inflammation. However, inflammatory renal disease may be mediated by extracellular purines, resulting in renal injury. The role of purinergic signaling is dependent on the concentrations of extracellular purines. Low basal levels of purines are important in normal homeostasis and growth. Concentrations of extracellular purines are significantly elevated during inflammation and mediate either an adaptive role or propagate local inflammation. Adenosine signaling mediates alterations in regional renal blood flow by regulation of the renal microcirculation, tubulo-glomerular feedback, and tubular transport of sodium and water. Increased extracellular ATP and renal P2 receptor-mediated inflammation are associated with various renal diseases, including hypertension, diabetic nephropathy, and glomerulonephritis. Experimental data suggests P2 receptor deficiency or receptor antagonism is associated with amelioration of antibody-mediated nephritis, suggesting a pathogenic (rather than adaptive) role of purinergic signaling. We discuss the role of extracellular nucleotides in adaptation to ischemic renal injury and in the pathogenesis of inflammatory renal disease.
Tanna A, Mcadoo S, Tam F, et al., 2013, Long-term outcome in patients with both ANCA and GBM positivity, PRESSE MEDICALE, Vol: 42, Pages: 667-668, ISSN: 0755-4982
Fish RS, Klootwijk E, Tam FWK, et al., 2013, ATP and arterial calcification., Eur J Clin Invest, Vol: 43, Pages: 405-412
BACKGROUND: Arterial calcification (AC) is a major health problem associated with extreme morbidity and a shortened survival. It is currently without any effective treatment. ATP and the purinergic system in general are now emerging as being important in the pathogenesis of AC and potentially provide a new focus for novel therapies. METHODS: This review systematically analyses and discusses the current literature examining the relevance of the purinergic system to AC. Particular emphasis is given to the enzymes associated with ATP metabolism and their role in maintaining a balance between promotion and inhibition of arterial mineralization. Points of controversy are highlighted, and areas for future research are suggested. CONCLUSION: The potential roles of ATP and the purinergic system in AC are beginning to be elucidated. While further work is necessary, current knowledge suggests that several components of the purinergic system could be targeted to develop new treatments for AC.
Tanna A, Laura G, Tam F, et al., 2013, Factors predictive of prognosis in renal AAV - A study of 104 patients in a single UK centre, PRESSE MEDICALE, Vol: 42, Pages: 670-671, ISSN: 0755-4982
Birch R, Scott-Ward T, Tam FWK, et al., 2013, Interdependent expression of P2X receptors in the mouse kidney: P2X4-P2X7 receptor "cross-talk", Joint Annual Meeting of the ASPET/BPS at Experimental Biology (EB), Publisher: FEDERATION AMER SOC EXP BIOL, ISSN: 0892-6638
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- Citations: 1
Kim MJ, Tam FWK, 2013, Currently available and potential future treatment options for IgA nephropathy, Expert Opinion on Orphan Drugs, Vol: 1, Pages: 625-635
Introduction: Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis throughout the world. The clinical presentation and disease progression is very variable and up to 30% of patients will progress to end-stage renal disease by 20 years. Despite improved understanding of the pathogenesis in the last decades, no disease-specific treatment is so far available. The aim of this review is to discuss the role of the currently available IgAN treatments and other new investigational and potential future treatment options. Areas covered: In the context of an updated overview of IgAN pathogenesis, the authors discuss currently available treatments in clinical practice, drugs under clinical investigation and potential new therapeutic agents. Expert opinion: Currently available treatment options for IgAN reduce surrogate markers of the disease progression and seem to slow the progression of disease to a certain degree. Researches on some pathogenesis-targeted therapeutic agents are in progress. To develop a new therapy, investigation of these agents in clinical trials in collaboration with pharmaceutical industry is essential. To consider these drugs as an orphan drug for IgAN would make it more achievable for the clinicians to perform clinical trials to investigate the efficacy of these drugs in patients with IgAN. © Informa UK, Ltd.
Deplano S, Cook HT, Russell R, et al., 2013, P2X7 receptor-mediated Nlrp3-inflammasome activation is a genetic determinant of macrophage-dependent crescentic glomerulonephritis, JOURNAL OF LEUKOCYTE BIOLOGY, Vol: 93, Pages: 127-134, ISSN: 0741-5400
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- Citations: 44
Kim MJ, McDaid JP, McAdoo SP, et al., 2012, Spleen Tyrosine Kinase Is Important in the Production of Proinflammatory Cytokines and Cell Proliferation in Human Mesangial Cells following Stimulation with IgA1 Isolated from IgA Nephropathy Patients, JOURNAL OF IMMUNOLOGY, Vol: 189, Pages: 3751-3758, ISSN: 0022-1767
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- Citations: 56
Fragiadaki M, Hill N, Hewitt R, et al., 2012, Hyperglycemia Causes Renal Cell Damage via CCN2-Induced Activation of the TrkA Receptor: Implications for Diabetic Nephropathy, Diabetes, Vol: 61, Pages: 2280-2288, ISSN: 0012-1797
CCN2, a secreted profibrotic protein, is highly expressed in diabetic nephropathy (DN) and implicated in its pathogenesis; however, the actions of CCN2 in DN remain elusive. We previously demonstrated that CCN2 triggers signaling via tropomyosin receptor kinase A (TrkA). Trace expression of TrkA is found in normal kidneys, but its expression is elevated in several nephropathies; yet its role in DN is unexplored. In this study we show de novo expression of TrkA in human and murine DN. We go on to study the molecular mechanisms leading to TrkA activation and show that it involves hypoxia, as demonstrated by ischemia–reperfusion injury and in vitro experiments mimicking hypoxia, implicating hypoxia as a common pathway leading to disease. We also expose renal cells to hyperglycemia, which led to TrkA phosphorylation in mesangial cells, tubular epithelial cells, and podocytes but not in glomerular endothelial cells and renal fibroblasts. In addition, we report that hyperglycemia caused an induction of phosphorylated extracellular signal–related kinase 1/2 and Snail1 that was abrogated by silencing of TrkA or CCN2 using small interfering RNA. In conclusion, we provide novel evidence that TrkA is activated in diabetic kidneys and suggest that anti-TrkA therapy may prove beneficial in DN.
Booth JWR, Tam FWK, Unwin RJ, 2012, P2 purinoceptors: Renal pathophysiology and therapeutic potential., Clin Nephrol, Vol: 78, Pages: 154-163, ISSN: 0301-0430
P2 purinoceptors, categorized into P2X and P2Y receptors, bind extracellular ATP and related di- and tri-phosphate nucleotides and are expressed throughout the kidney. P2X receptors are non-selective cation channels and P2Y receptors are metabotropic G protein-coupled receptors. Both families may couple to a range of second messenger systems and provoke outcomes including cell proliferation, cytokine secretion, membrane channel regulation and cell death. The cellular response to ATP release may vary widely and depends on both the pattern of local receptor expression and the action of ectonucleotidases altering agonist availability, creating a finely tuned network. P2 signaling participates in disparate physiological processes, including control of water and solute transport and autoregulation of renal blood flow. Given the ubiquity, complexity and diversity of the P2 network, it is not surprising that P2 signaling also contributes to mechanisms of renal disease. This review summarizes the current evidence for P2 receptor involvement in a range of kidney diseases, and highlights areas that may lead to potential therapeutic advances. Particular attention is paid to the pro-inflammatory P2X7 receptor, currently at the heart of renal P2 pathophysiology and for which selective receptor antagonists are now available.
Vilasi A, Deplano S, Deplano S, et al., 2012, PHOSPHOPROTEOMIC ANALYSIS OF THE P2X7 SIGNALLING CASCADE IN MACROPHAGES: A PUTATIVE ROLE IN GLOMERULONEPHRITIS, 49th Congress of the European-Renal-Association/European-Dialysis-and-Transplant-Association (ERA-EDTA), Publisher: OXFORD UNIV PRESS, Pages: 80-81, ISSN: 0931-0509
Fenske WK, Dubb S, Bueter M, et al., 2012, Effect of bariatric surgery-induced weight loss on renal and systemic inflammation and blood pressure: a 12-month prospective study, SURGERY FOR OBESITY AND RELATED DISEASES, Vol: 9, Pages: 559-568, ISSN: 1550-7289
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- Citations: 102
Kim MJ, TAM F, 2011, Urinary monocyte chemoattractant protein-1 in renal disease, Clin Chim Acta, Vol: 412, Pages: 2022-2030
Monocyte chemoattractant protein-1 (MCP-1/CCL2) has a critical role in the development of various renal diseases. Data from disease specific experimental animal models and clinical studies confirm that MCP-1 plays an important part in the pathogenesis of renal diseases. The action of MCP-1 in these studies has been shown to be more complex than the traditional concept of monocyte/macrophage recruitment to the inflammatory site. MCP-1 is expressed in renal tissues and it is detectable in urine of patients with a variety of renal diseases. Measurement of urinary levels of MCP-1 can provide valuable information not only for the diagnosis of active renal disease, but also for monitoring of response to therapy. Urinary MCP-1 measurement can provide help with evaluation of the prognosis in various renal diseases. Furthermore, selective targeting of MCP-1 could be an effective treatment in suppressing a number of renal diseases as blocking MCP-1 has already been shown to ameliorate renal diseases in experimental animal models. The advantage of measuring urinary MCP-1 rather than the conventional markers must now be validated using a larger cohort of patients in different renal diseases. Also the therapeutic potential of MCP-1 targeting agents needs to be investigated in clinical studies.
Kim MJ, 2011, Oral cholecalciferol decreases albuminuria and urinary TGF-β1 in patients with type 2 diabetic nephropathy on established renin-angiotensin-aldosterone system inhibition., Kidney Int 2011 Oct(8):851-60 PMID: 21832985
Arulkumaran N, Unwin RJ, Tam FWK, 2011, A potential therapeutic role for P2X7 receptor (P2X7R) antagonists in the treatment of inflammatory diseases, EXPERT OPINION ON INVESTIGATIONAL DRUGS, Vol: 20, Pages: 897-915, ISSN: 1354-3784
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- Citations: 212
Kim MJ, Frankel AH, Tam FW, 2011, Urine proteomics and biomarkers in renal disease, Nephron Experimental Nephrology, Vol: 119, Pages: e1-e7, ISSN: 0028-2766
The application of urine proteomics is a useful approach to the study of the proteins involved in healthy and diseased kidneys and may provide a noninvasive approach to assess disease activity and to monitor clinical response in patients with renal diseases. This technique may provide an additional tool in clinical trials and for the assessment of prognosis for patients. Both soluble proteins and membrane-bound (exosomal) proteins may be studied, and multiple approaches are available. Discovery proteomics is an unbiased approach to detect novel proteins in urine samples. Mass spectrometry (MS) is often needed to identify specific protein fragments. Targeted proteomics often involves specific immunoassays or modified MS, which enables a hypothesis-based design. These approaches may be integrated. For example, specific proteins may be identified by the discovery approach or laboratory study of disease mechanisms. These proteins will then be studied further by targeted proteomics. In order to translate to clinical practice, the specific assays need vigorous validation by means of sufficiently statistically powered clinical trials.
Sheryanna AM, Smith J, Bhangal G, et al., 2011, Treatment with a cyclin-dependent kinase inhibitor, seliciclib, is effective in reducing glomerular macrophage numbers and the severity of established experimental glomerulonephritis, NEPHROLOGY, Vol: 16, Pages: 410-416, ISSN: 1320-5358
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- Citations: 8
McAdoo SP, Tam FWK, 2011, FOSTAMATINIB DISODIUM <i>Tyrosine</i>-<i>Protein Kinase SYK</i>/<i>FLT3 Inhibitor</i> <i>Treatment of Rheumatoid</i> <i>Arthritis Oncolytic</i>, DRUGS OF THE FUTURE, Vol: 36, Pages: 273-280, ISSN: 0377-8282
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- Citations: 40
Bueter M, Ashrafian H, Fra, et al., 2011, Sodium and water handling after gastric bypass surgery in a rat model, Surg Obes Relat Dis
McAdoo SP, Tam FWK, 2011, Fostamatinib Disodium., Drugs Future, Vol: 36, ISSN: 0377-8282
The non-receptor tyrosine kinase Syk has a diverse range of biological functions, including a critical role in the intracellular signalling cascade for the surface immunoglobulin receptor on B lymphocytes, and the Fc receptor expressed on numerous immune effector cells. It is therefore seen as a potential therapeutic target in a variety of conditions, including autoimmune, allergic and malignant diseases. Fostamatinib disodium is the orally bioavailable prodrug of R406, a relatively selective small molecule inhibitor of Syk, that has accordingly shown activity in numerous cell types in vitro, and efficacy in a remarkable range of animal models in vivo, including rodent models of asthma, inflammatory arthritis, lupus, glomerulonephritis, diabetes and lymphoma. Success in these models has translated to phase II clinical trials in autoimmune thrombocytopenia, lymphoma and, most notably, rheumatoid arthritis, in which larger phase III trials are currently in progress. Whilst the diverse biological functions of Syk, coupled to the potential off-target effects of this kinase inhibitor are a source of possible toxicity, the available data thus far augurs well for future clinical use of Fostamatinib in a wide range of human diseases.
Ahmad S, North BV, Qureshi A, et al., 2010, CCL18 in peritoneal dialysis patients and encapsulating peritoneal sclerosis, EUROPEAN JOURNAL OF CLINICAL INVESTIGATION, Vol: 40, Pages: 1067-1073, ISSN: 0014-2972
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- Citations: 19
Bueter M, Dubb SS, Gill A, et al., 2010, Renal Cytokines improve early after bariatric surgery, Br J Surg.
Stangou M, Bhangal G, Lai P-C, et al., 2010, Effect of IL-11 on glomerular expression of TGF-beta and extracellular matrix in nephrotoxic nephritis in Wistar Kyoto rats, JOURNAL OF NEPHROLOGY, Vol: 24, Pages: 106-111, ISSN: 1121-8428
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- Citations: 9
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