|Inflammation and dyslipidaemia||Dr Xiong Ruan and Dr David Wheeler|
|Progressive renal disease||Dr Jill Norman|
|Renal physiology||Professor Robert Unwin|
|Renal transport proteins||Professor Robert Unwin|
||Dr Mark Little and Dr Alan Salama|
|Polycystic kidney disease||Professor Pat Wilson|
Inflammation and dyslipidaemia
Inflammation and dyslipidaemia co-exist in patients with chronic kidney disease. This project examines how these two factors may interact to contribute to progression of kidney injury and the premature development of arterial disease. Our results show that inflammatory cytokines disrupt intracellular lipid metabolism thereby causing intracellular lipid accumulation (foam cell formation). This is the result of both excess lipid uptake and impaired lipid export from the cell. On-going work is investigating the mechanisms by which a cell is able to "sense" its intracellular lipid cholesterol level and respond accordingly, a process that involves sterol regulatory element binding protein (SREBP) cleavage activating protein (SCAP). Importantly, pharmaceutical compounds that stimulate peroxisome proliferator activator receptors (PPARs) appear to protect against intracellular lipid accumulation. Dr Zac Varghese is also involved in studying the involvement of lipids in chronic allograft nephropathy and the anti-inflammatory and anti-atherosclerotic effects of specific immunosuppressive drugs.
Dr Xiong Ruan, Dr David Wheeler and Dr Zac Varghese
Progressive renal disease
The aim of this work is to investigate the cellular and molecular mechanisms underlying the pathogenesis of progressive fibrosis of the kidney, which is the cardinal feature of chronic kidney disease. Although many progressive diseases are glomerular in origin, it is tubulointerstitial involvement that best predicts progression. In understanding how glomerular injury is transmitted to the tubulointerstitium, our group has suggested an important role for hypoxia; an idea formalised as the Chronic Hypoxia Hypothesis (Fine et al Kidney Int, 53 Suppl 65:S74-S78, 1998). In support of this hypothesis, in vivo, in a model of progressive renal disease, tissue hypoxia precedes renal scarring and in vitro studies have demonstrated that hypoxia (1% O2) can promote a fibrogenic phenotype in tubular epithelial cells and renal fibroblasts. Current studies are centred on understanding of the role of hypoxia in the pathogenesis of renal fibrosis. Specific areas of investigation include the mechanisms of hypoxic regulation of expression of fibrogenic genes; the control of fibroblast to myofibroblast differentiation; and the role of fibroblast-endothelial cell interactions in the pathogenesis of fibrosis. Another aspect of the work has been investigating the effects of isoprostanes (products of non-enymatic lipid peroxidation and validated markers of oxdative stress) on endothelial cell function. Our recent in vitro data has revealed a potential anti-inflammatory effect of isoprostanes in suppressing adhesion of monocytes to microvascular endothelial cells. On-going studies are investigating the mechanisms and mediators underlying this novel role for isoprostanes in the microvasculature.
Dr Jill Norman
The research group led Prof. Unwin and Drs Debnam and Shirley is broadly engaged in studies of renal and intestinal transport physiology and pathophysiology, which includes gut-renal interactions in phosphate, glucose, and iron homeostasis (with Prof. Kaila Srai, UCL Structural and Molecular Biology), clinical fluid and electrolyte disorders (including genetic and acquired tubulopathies) and renal stone disease. A specific area of interest is the potential for an 'intracrine' regulatory system of renal tubular fluid and solute transport that is dependent on the bioactive components of tubular fluid, such as small peptides (including cytokines) and nucleotides (such as ATP). On-going studies are focused on the handling of filtered low molecular weight proteins and peptides in the renal Fanconi syndrome, and the application of novel spectroscopic methods to determining tubular fluid composition. The group, with its main collaborators (Dr Scott Wildman, Royal Veterinary College and Dr Frederick Tam, Imperial College London), is also characterising the renal ATP-sensitive P2 receptor system and its involvement in collecting duct sodium and water transport, and in renal injury and inflammation.
Professor Robert Unwin
Renal transport proteins
The activity of a number of transport proteins in the nephron are modified by the tubular perfusion of adenosine 5'-triphosphate (ATP) even though they themselves are insensitive to extracellular ATP. Thus, activation of an abundance of cell-surface ATP-gated receptors, known as P2 receptors, by endogenous ATP (secreted from cells as an autocrine or paracrine factor) has been proposed to indirectly regulate renal solute and water transporter activity.
In my laboratory, I investigate interactions between ATP-gated receptors (P2 receptors) and renal transport proteins using two experimental approaches. Firstly, I explore the molecular mechanisms of receptor/channel interactions in isolation in the Xenopus oocyte expression system by co-expressing transport proteins and P2 receptors (based on RT-PCR and immunohistochemical data), using twin-electrode electrophysiology. Secondly, I investigate transport activity in response to extracellular ATP in the apical membrane of intact cells of the rat collecting duct (CD), using the microdissected isolated split-open tubule technique and patch clamp electrophysiology. We have international collaborations with groups in New York (USA), Lausanne (Switzerland) and Nijmegen (The Netherlands).
Professor Robert Unwin and Dr Anselm Zdebik
We are a translational research group with the overall aim of improving understanding of the immunopathogenic mechanisms of glomerulonephritis, with a specific focus on the autoimmune disease ANCA associated vasculitis. This is the commonest cause of rapidly progressive glomerulonephritis and is associated with autoimmunity directed against components of the neutrophil cytoplasm. The driving force behind this aim is the clinical need for biomarkers that accurately identify active vasculitis, and which predict those in whom immunosuppressive therapy can be withdrawn safely. To achieve this aim we are interested in addressing the following research questions:
- What is the molecular basis for the innate immune dysfunction observed in this disease, in particular in relation to neutrophils and the monocyte/macrophage system?
- What cross talk occurs between the innate and adaptive immune systems to perpetuate the disease process, or to induce immune tolerance, in ANCA associated vasculitis?
- What is the immunopathogenic difference between anti-MPO and anti-PR3 antibody associated systemic vasculitis?
- What is the interplay between clinical and genetic characteristics in determining the outcome, response to therapy, risk of relapse and incidence of adverse events in patients with ANCA associated vasculitis?
To address these questions we use a range of research tools, including in vitro cell culture systems, novel animal models of systemic vasculitis and a pan-UK vasculitis registry that links detailed longitudinal clinical data with a DNA, urine, serum and tissue bio-repository. The Renal Inflammation Group laboratory is intimately associated with the Royal Free Hospital Vasculitis clinic, which provides a multi-disciplinary tertiary referral service to patients with vasculitis and SLE.
Dr Mark Little and Dr Alan Salama
Polycystic kidney disease
Autosomal Polycystic Kidney Diseases (ADPKD and ARPKD) affect >12 million patients world-wide and lead to endstage renal failure with a wide range in age of onset. The overall goal of our research is to translate a basic understanding of molecular, cellular and developmental mechanisms of AD- and ARPKD in cell lines and animal models into retardation therapies for application in patients. Our current projects focus on:
- The analysis of the functions and interactions of cystic proteins (PC-1, PC-2 and FC-1) in normal renal epithelial cell proliferation, differentiation, polarisation, cytoskeletal organization and morphogenesis and how mutations in PKD1, PKD2 and PKHD1 compromise those processes.
- The characterization of ADPKD-associated fibrosis with respect to the molecular/cellular properties and epithelial interactions of their fibroblasts and endothelial cells as a basis for biomarker and therapeutic development.
- The direct, comparative evaluation, optimisation and application of inhibitors of the ErbB family of growth factor receptors as therapeutic targets for PKD using human PKD cell lines and genotypic mouse models.
- Development of an ADPKD disease patient registry for cohort analysis and clinical trial development.
Professor Pat Wilson