Mark Dockrell

Mark Dockrell
Epsom and St Helier University Hospitals NHS Trust · Department of Nephrology

Doctor of Philosophy

About

64
Publications
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1,969
Citations

Publications

Publications (64)
Article
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The intensifying worldwide spread of mycotoxigenic fungal species has increased the possibility of mycotoxin contamination in animal feed and the human food chain. Growing evidence shows the deleterious toxicological effects of mycotoxins from infants to adults, while large population based screening programs are often missing to identify affected...
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Renal risk stratification in systemic immunoglobulin light‐chain (AL) amyloidosis is according to estimated glomerular filtration rate (eGFR) and urinary protein creatinine ratio (uPCR), the latter attributed to glomerular dysfunction, with proximal tubular dysfunction (PTD) little studied. Urinary retinol binding protein 4 (uRBP), a low molecular...
Article
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Background: In the kidney glucose is freely filtered by the glomerulus and, mainly, reabsorbed by sodium glucose cotransporter 2 (SGLT2) expressed in the early proximal tubule. Human proximal tubule epithelial cells (PTECs) undergo pathological and fibrotic changes seen in diabetic kidney disease (DKD) in response to elevated glucose. We developed...
Article
Background- Retinol-binding protein4 (RBP) assays using polyclonal antibodies (pRBP) have major problems of non-linearity of dilution and a very small useable dynamic range. Our objective was to develop a specific assay with a wider dynamic range to detect tubular proteinuria. Methods: mRBP (monoclonal capture and second antibody with colorimetric...
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Introduction Albuminuric and non-albuminuric pathways contribute to diabetic kidney disease (DKD). Proximal tubule and inflammation play important roles in these processes. There is a need for urinary biomarker/s to detect early kidney damage and predict progression. Methods Nine urinary biomarkers were measured at baseline in 400 patients with di...
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Background and Aims Cardiovascular morbidity and mortality are increased in kidney transplant patients. High blood pressure (BP) contributes significantly to this risk and is associated with shortened allograft survival. Dietary salt reduction is widely recommended as a strategy to lower BP in the general population and in chronic kidney disease. D...
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Airway epithelial tight junction (TJ) proteins form a resistive barrier to the external environment, however, during respiratory bacterial infection TJs become disrupted compromising barrier function. This promotes glucose flux/accumulation into the lumen which acts as a nutrient source for bacterial growth. Metformin used for the treatment of diab...
Article
Alternative splicing is an important gene regulation process to distribute proteins in health and diseases. Extra Domain A+ Fibronectin (EDA+Fn) is an alternatively spliced form of fibronectin (Fn) protein, present in the extra cellular matrix (ECM) and a recognised marker of various pathologies. TGFβ1 has been shown to induce alternative splicing...
Article
Alternative splicing is a fundamental phenomenon to build protein diversity in health and diseases. Extra Domain A+ Fibronectin (EDA+Fn) is an alternatively spliced form of fibronectin protein present in the extra cellular matrix (ECM) in renal fibrosis. Podocytes are spectacular cell type and play a key role in filtration and synthesise ECM protei...
Article
The interactions of the extracellular matrix (ECM) proteins with cells strongly regulate cell behaviour. The glomerular basement membrane (GBM) is a dynamic structure made up of protein secreted by endothelial cells and podocyte. These proteins could regulate the behaviour of these cells in health and diseases. Extra Domain A + Fn (EDA+Fn) is an al...
Article
Growth factors like TGFβ and CTGF (CCN2) plays a vital role in various cellular functions. TGFβ and CTGF are overexpressed in renal fibrosis. CTGF act as profibrotic stimuli to TGFβ. CCN3 is a member of CCN family which also comprises CCN1 (CYR61), CCN2 (CTGF), CCN4 (WISP-1), CCN5 (WISP-2) and CCN6 (WISP-3). CCN3 has been shown to antagonise CTGF....
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The EDA+ splice variant of fibronectin (Fn) is an early and important component of the extracellular matrix in renal fibrosis. In this work, we investigate cellular mechanisms of EDA+ Fn production in human primary proximal tubule epithelial cells (PTECs).TGFβ1-induced EDA+Fn production was assessed by immunocytochemistry, PCR and Western blotting....
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Background: Podocytes are highly specialized cells integral to the normal functioning kidney, however, in diabetic nephropathy injury occurs leading to a compromised phenotype and podocyte dysfunction which critically produces podocyte loss with subsequent renal impairment. TGFβ1 holds a major role in the development of diabetic nephropathy. Erk5 i...
Article
Introduction Crohn’sDisease is a chronic autoimmune condition characterised by abdominal pain and diarrhoea. 80% of patients will require surgery and half of these will be as a result of stricture formation. Strictures occur as a result of mesenchymalcell proliferation and deposition of extracellular matrix. Epithelial-mesenchymaltransition (EMT) i...
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The basic-Helix-Loop-Helix family (bHLH) of transcriptional factors plays a major role in regulating cellular proliferation, differentiation and phenotype maintenance. The downregulation of one of the members of bHLH family protein, inhibitor of DNA binding 2 (Id2) has been shown to induce de-differentiation of epithelial cells. Opposing regulators...
Data
TGFβ1 downregulation of Id2 was not prevented by Smad3 knock-down. HKC 8 cells were transfected with Smad3 siRNA or negative control siRNA for 24 h. After 24 h serum recovery and 24 h serum free period, the cells were treated with either vehicle (0.1% BSA) or TGFβ1 (5 ng/ml) for a further 24 h. The cells were lysed and the Id2 and Smad3 expressions...
Data
BMP 7 induction of Id2 was not prevented by Smad1 knock-down. HKC 8 cells were transfected with either Smad1 siRNAs or negative control siRNA for 24 h. After 24 h serum recovery and 24 h serum free period, the cells were treated with either vehicle (0.1% BSA) or BMP 7 (200 ng/ml) for a further 18 h. The cells were lysed and Id2 and Smad1 expression...
Data
TGFβ1 downregulation of Id2 was not prevented by Smad2 knock-down. HKC 8 cells were transfected with Smad2 siRNA or negative control siRNA for 24 h. After 24 h serum recovery and 24 h serum free period, the cells were treated with either vehicle (0.1% BSA) or TGFβ1 (5 ng/ml) for a further 24 h. The cells were lysed and the Id2 and Smad2 expressions...
Article
The aim of this study was to determine the validity and reliability of the Malnutrition Universal Screening Tool (MUST) and the Malnutrition Screening Tool (MST) in hospital inpatients with renal disease. A cross-sectional and longitudinal study. The study took place on 3 renal inpatient wards in a tertiary hospital in south London. A total of 276...
Article
Renal physiology and pathology are complex systems that are best studied in whole living organisms. This, however, is often restricted by our desire to limit the number of animal experiments undertaken and to replace them with relevant in vitro models that can be used as surrogates for the system under test. Primary culture cells are derived direct...
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Blood pressure is a heritable trait influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (?140?mm?Hg systolic blood pressure or? ?90?mm?Hg diastolic blood pressure). Even small increments in blood pressure are associated with an increased risk of cardiovascular events...
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Using genome-wide association, we identify common variants at 2p12-p13, 6q26, 17q23 and 19q13 associated with serum creatinine, a marker of kidney function (P = 10(-10) to 10(-15)). Of these, rs10206899 (near NAT8, 2p12-p13) and rs4805834 (near SLC7A9, 19q13) were also associated with chronic kidney disease (P = 5.0 x 10(-5) and P = 3.6 x 10(-4), r...
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Connective tissue growth factor (CTGF, CCN2) is a key mediator of tissue fibrosis. CCN2 plays an important role in the development of glomerular and tubulointerstitial fibrosis in progressive kidney diseases. In this review, we discuss the biology of CCN2 with a focus on the regulation of CCN2 gene, cellular mechanisms of profibrotic CCN2 effects a...
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Chronic kidney diseases are characterized by progressive tubulointerstitial fibrosis, and TGFbeta1 plays a crucial role in its development. Bone morphogenic protein 7 (BMP 7), another member of the TGF superfamily, antagonized the profibrotic effects of TGFbeta1, including epithelial mesenchymal transition and E-cadherin loss, in the previous studi...
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Bacterial lipopolysaccharides (LPS) are potent inducers of proinflammatory signaling pathways via the activation of nuclear factor-kappa B (NF-κB) and mitogen-activated protein kinase (MAPK), causing changes in the processes that control lung fluid homeostasis and contributing to the pathogenesis of lung disease. In human H441 airway epithelial cel...
Article
To evaluate a new range of chromogenic substrates for the detection of beta-galactosidase activity in coliforms and to compare their performance in agar media and broths. Sixteen novel galactoside substrates were prepared and incorporated into agar and broth. Their performance was compared using Escherichia coli (five strains), Salmonella (two stra...
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Irrespective of the exposure measure and the confounders controlled for, diabetes was consistently found to be associated with an increased risk of TB. This study may underestimate the true association between the two diseases, due mainly to exposure misclassification, as only 24.8% of the sample took the OGTT. Due to the inclusion of ''ever diagno...
Article
Transforming growth factor (TGF) beta is strongly implicated in the progression of renal fibrosis. TGFbeta1 is reported to cause epithelial-mesenchymal transition, inhibition of epithelial cell proliferation, increased apoptosis, auto-induction of TGFbeta production and induction of secondary mediators of tissue fibrosis such as connective tissue g...
Article
Proximal tubule epithelial cells (PTECs) release proinflammatory and profibrogenic mediators when exposed to serum albumin that may contribute to progression of kidney disease. Interleukin 6 (IL-6) may influence renal fibrosis by modulating transforming growth factor beta1 (TGFbeta1) signalling. PTECs have been demonstrated to produce IL-6 in respo...
Article
The role of the MAP kinase, extracellular signal-regulated kinase 5 (ERK5) remains unknown, however it is involved in cell differentiation and survival as highlighted by the embryonic lethality of the ERK5 knockout. ERK5 can be activated by growth factors and other extracellular signals. TGF-beta, a powerful controller of epithelial cell phenotype,...
Article
Bone morphogenic protein-7 (BMP-7) is a member of the transforming growth factor beta (TGFbeta) superfamily involved in organogenesis. Recent work suggests that BMP-7 can reverse the fibrotic effects of TGFbeta but the underlying mechanism is unknown. We sought to determine BMP-7 signaling and its modulation of TGFbeta induced fibrotic outcomes in...
Article
Albumin has been shown to activate the mitogen activated protein kinase (MAPK) pathway in proximal tubular cells (PTECs) of the kidney. Megalin, the putative receptor for albumin has potential signalling properties. However, the mechanisms by which megalin signals are unclear. The adaptor phosphoprotein Disabled-2 (Dab2) is known to interact with t...
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Proteinuria predicts the decline of renal function in chronic kidney disease. Reducing albuminuria has been shown to be associated with a reduction in this rate of decline. Proximal tubular epithelial cells (PTECs), when exposed to albumin produce matrix proteins, proinflammatory and profibrotic cytokines like TGF-beta(1). Some of these effects are...
Article
Transforming growth factor beta 1 (TGFbeta1) is a fibrokine implicated in the progression of renal fibrosis. Following TGFbeta1 receptor activation, a number of signalling pathways are stimulated. This study investigates the role of p38 mitogen-activated protein (MAP) kinase and Smad pathways in the TGFbeta1-induced fibronectin (FN) production. Tra...
Article
Exogenous tracer-based methods of measuring glomerular filtration rate (GFR) are difficult to perform, whilst creatinine-based estimation formulae are inaccurate. We assessed a new technique of measuring iohexol clearance using timed dried capillary blood spots. A reference GFR was measured in 81 subjects (GFR 15-124 ml/min/1.73 m(2)) by iohexol cl...
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Development of an outpatient finger-prick glomerular filtration rate (GFR) procedure suitable for epidemiological studies. In clinical practice, reference GFR procedures are rarely used; in large-scale research studies, a great deal of effort and experience is required to obtain them, which is a considerable disincentive to using GFR as an end poin...
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In chronic renal diseases, progressive loss of renal function correlates with advancing tubulo-interstitial fibrosis. TGFbeta1-Smad (transforming growth factor-beta1-Sma and Mad protein) signalling plays an important role in the development of renal tubulo-interstitial fibrosis. Secretion of CTGF (connective-tissue growth factor; CCN2) by PTECs (pr...
Article
Ras monomeric GTPases are pivotal to many core cellular processes such as proliferation and differentiation. The post-translational prenylation of Ras with a farnesyl or a geranylgeranyl moiety is thought to be critical for its membrane binding and consequent signaling activity. Inhibitors of Ras prenylation have an anti-proliferative effect in som...
Article
Connective tissue growth factor (CTGF, CCN2) plays a fundamental role in the development of tissue fibrosis by stimulating matrix deposition and mediating many of the pro-fibrotic effects of transforming growth factor (TGF)-beta. CCN2 induction by TGF-beta in renal proximal tubule epithelial cells (PTECs) is likely to play an important role in the...
Article
There is increasing evidence that extracellular ATP acting on purinoceptors may play an important signalling role in renal epithelial cells, often through alterations in cellular Ca(2+). In this paper effects of extracellular ATP and related purinoceptor agonists and antagonists on [Ca(2+)](i) have been studied in single cells from primary cultures...
Article
The proliferation of renal fibroblasts is implicated in the pathophysiologic processes of renal fibrosis. Many of the growth factors involved in proliferation are known to activate intracellular signaling pathways that converge on Ras monomeric GTPases. Although three ras family genes exist, their functional specificity is not yet known. Using anti...
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Background: End-stage renal failure is associated with a low-output cardiomyopathy, left ventricular hypertrophy and increased QTc dispersion. Cardiac dysfunction is prevalent in patients at the beginning of dialysis and is an important predictor of mortality. Ca(2+) influx through voltage-gated L-type Ca(2+) channels plays a key role in the excit...
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Progressive renal fibrosis is driven by a range of cytokines that act via membrane receptors and intracellular signaling cascades to evoke gene transcription events and related responses. The Ras family of GTPases has been implicated in many of these signaling cascades in model systems such as 3T3 fibroblasts. However, the roleof the specific Ras i...
Article
In essential hypertension, abnormal platelet function may induce vasospasm and predispose to thrombotic vascular occlusion. We studied in vitro aggregability in platelets from young men with contrasting predisposition to hypertension, defined by their own blood pressure and blood pressures of their parents. Among offspring of parents with low blood...
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The physiological role of endogenous nitric oxide in regulation of renal function in humans is unclear. Eight healthy men received an inhibitor of nitric oxide synthase, N(G)-monomethyl-L-arginine (L-NMMA, 3 mg/kg), and saline placebo intravenously on two occasions. L-NMMA significantly increased mean arterial pressure (+7%) and total peripheral re...
Article
Endothelins modulate in vitro aggregation of human platelets in a bi-directional manner. Thus endothelin-1 has been shown to act as a potentiator of primary aggregation and an inhibitor of secondary aggregation. The endothelin receptors and corresponding second messengers which cause these effects have not yet been characterised. This study investi...
Article
To elucidate the sequential mechanisms underlying cyclosporin-induced hypertension and nephrotoxicity. A study of healthy males over the first 9 days of drug ingestion to permit the detection of serial changes in renal function and blood pressure in a situation free from the confounding variables of concomitant disease or drugs. Double-blind, place...
Article
Endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by endothelial cells. We investigated whether ET-1, like other potent endothelium-derived vasoactive agents, interacts directly with human platelets in vitro. Platelet-rich plasma was obtained from healthy male volunteers and incubated with ET-1 (1 microM) or vehicle (sodium chloride...
Article
Endothelin-1 (ET-1) causes long-lasting vasoconstriction associated with a prolonged elevation of intracellular free Ca2+. Because this may be mediated through an effect on membrane ion channels, we investigated the effects of the dihydropyridine calcium channel antagonist nifedipine; two structurally distinct K+ channel openers, pinacidil and levc...
Article
Endothelin-1 (ET-1) is a potent vasoconstrictor peptide produced by endothelial cells. We investigated whether ET-1, like other potent endothelium-derived vasoactive agents, interacts directly with human platelets in vitro. Platelet-rich plasma was obtained from healthy male volunteers and incubated with ET-1 (1 [mu]M) or vehicle (sodium chloride 1...
Article
Binding of [125I]-labelled endothelin-1 (ET-1) to rat cardiac membranes and the effects of endothelin-1 (ET-1), endothelin-3 (ET-3), the calcium channel antagonist nifedipine, and both enantiomers of the potassium channel opener cromakalim (BRL 34915) on binding have been examined. Specific binding of [125I]-ET-1 was inhibited in a concentration de...
Article
We have investigated the effect of varying sodium intake on the renin-angiotensin system, ADP-induced patelet aggregationin vitro, and blood 5-HT concentrations in 9 male volunteers. Systolic blood pressure was slightly reduced during a low sodium diet, whereas the diastolic pressure remained unchanged. Plasma renin activity and aldosterone concent...

Questions

Question (1)
Question
I'm interested in looking at mechanisms of activation of the whole complex

Projects

Projects (6)
Project
The goals are to better understand the role of K Cadherin in regulating human proximal tubule function and define its role in renal diseases including diabetic kidney disease, renal fibrosis and Renal Cell Carcinoma.
Project
TGF-beta 1 mediated alternative splicing Extra domain A Fibronectin in podocytes. Signalling pathways involved in alternative splicing of Extra domain A Fibronectin in podocytes.