Cellular basis of Albuminuria

Lead Research Organisation: University of Bristol
Department Name: Clinical Science at North Bristol

Abstract

The kidney cleans the blood via a filtration process and in kidney disease this process is disrupted, allowing proteins to escape into the urine (albuminuria). Over time this disease results in the destruction of the kidney resulting in the patient requiring dialysis and ultimately a kidney transplant. In diabetes, damage to the kidney filtration barrier (diabetic nephropathy) is a major complication and as a result of the current diabetes epidemic it is now the most common cause of kidney failure in the Western world. Although the link between diabetes and kidney failure is not understood, the progression of diabetic nephropathy follows a predictable clinical course. Initially, the kidneys leak small amounts of protein, and as the kidneys deteriorate further this amount increases. At present our understanding of how the kidney?s filters work and how diabetes causes damage is poor. The kidney?s filters consist of two cell types called podocytes and endothelial cells which interact together to form the filter. We can grow both cell types within our laboratory and the aim of our project is to understand how these cells interact and communicate with each other to form the filter in a healthy individual, and how this healthy state is disrupted during diabetes. Also we are trying to grow these cells together so that we can simulate the kidney?s filters in the laboratory and understand the filtration function of the kidney and how this is damaged in renal disease. We are studying two novel forms of treatment that can reduce albuminuria: learning how they achieve this will help us to design and develop new therapeutic approaches to deal with this problem.

Technical Summary

Clinical importance of albuminuria is widely accepted, being a cardinal sign of kidney disease and a marker of cardiovascular risk in both diabetic and non-diabetic populations. However, cellular mechanisms underlying albuminuria are still unclear. The renal glomerular capillary wall allows passage of water and small molecules but in healthy individuals prevents passage of albumin and other key proteins, functioning as a complex biological sieve. It has a unique 3-layer structure: inner glomerular endothelium with glycocalyx and fenestrations, underlying glomerular basement membrane, and outer (urinary side) podocytes with characteristic foot processes linked by slit diaphragms. Mutations in genes encoding podocyte-specific proteins expressed at slit diaphragms (e.g. nephrin, podocin) cause congenital nephrotic syndrome; disturbances of slit diaphragms may be important in diabetic nephropathy and other acquired diseases, as may dysfunction of GBM and/or glomerular endothelium. In work currently funded by MRC we have utilised our unique human glomerular endothelial and podocyte cell lines to study phenotype and function of these two cells plus interactions between them. We now propose to extend our mechanistic understanding of the cellular responses, especially intracellular signalling pathways involved, increase sophistication of our in vitro model systems, continue our in vivo validation work in rodents (mostly in collaborative work that is separately funded) and move towards translational application of our results into anti-proteinuric therapies. In particular we will focus on (1) insulin and insulin-like growth factor-induced signalling and the effects on these of culture conditions designed to mimic diabetes mellitus, using mutant and reconstituted cell lines to analyse the role of nephrin and podocin in these responses; (2) engineering the glomerular capillary wall in vitro including studies of glomerular endothelial glycocalyx and fenestrations; and (3) study of modes of action of the anti-proteinuric agents sulodexide and interferon Beta. Via our unique cellular resources, experience and skills accumulated in recent years and a network of international collaborations allowing in vivo validation work, our results will move us from cell-based studies towards therapeutic targets in an area of major clinical significance.

Publications

10 25 50
publication icon
Arora S (2009) Human immunodeficiency virus downregulates podocyte apoE expression. in American journal of physiology. Renal physiology

publication icon
Asgeirsdóttir SA (2012) MicroRNA-126 contributes to renal microvascular heterogeneity of VCAM-1 protein expression in acute inflammation. in American journal of physiology. Renal physiology

publication icon
Asgeirsdóttir SA (2010) Targeted transfection increases siRNA uptake and gene silencing of primary endothelial cells in vitro--a quantitative study. in Journal of controlled release : official journal of the Controlled Release Society

publication icon
Boor P (2010) PDGF-C mediates glomerular capillary repair. in The American journal of pathology

 
Description BBSRC project grant
Amount £300,000 (GBP)
Organisation Biotechnology and Biological Sciences Research Council (BBSRC) 
Sector Public
Country United Kingdom
Start 04/2009 
End 03/2012
 
Description Diabetes UK Project Grant
Amount £170,000 (GBP)
Organisation Diabetes UK 
Sector Charity/Non Profit
Country United Kingdom
Start 02/2010 
End 01/2013
 
Description KRUK Project Grant
Amount £140,000 (GBP)
Organisation Kidney Research UK 
Sector Charity/Non Profit
Country United Kingdom
Start 12/2010 
End 11/2012
 
Description MRC Clinical Research Training Fellowship
Amount £285,000 (GBP)
Organisation Medical Research Council (MRC) 
Sector Public
Country United Kingdom
Start 08/2010 
End 07/2013
 
Description Wellcome Trust Project Grant
Amount £160,000 (GBP)
Organisation Wellcome Trust 
Sector Charity/Non Profit
Country United Kingdom
Start 09/2010 
End 08/2012
 
Title Unique human glomerular cell lines 
Description Publications as cited 
Type Of Material Cell line 
Year Produced 2006 
Provided To Others? Yes  
Impact Recognition of our scientific contribution in generating these research reagents and making them available to collaborators. Numerous joint publications. 
 
Description Numerous research collaborations worldwide 
Organisation Albert Einstein College of Medicine
Country United States 
Sector Academic/University 
PI Contribution Our cell lines remain in great demand and we continue to add new collaborators to our list.
Collaborator Contribution Mutual laboratory visits for training/information and collaborative work. Ongoing research collaboration.Research collaborationOngoing research collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaboration Research collaboration
Impact Publications include PMIDs 20889126, 20375988, 19902259, 19766679, 19737241, 19703278, 19584399, 19553347, 19515812, 19383602, 19233685, 19124603 and all other more recent ones listed under publications. Multidisciplinary including basic laboratory scientists, medically qualified laboratory scientists and pure clinicians.
Start Year 2008
 
Description Numerous research collaborations worldwide 
Organisation Imperial College London
Department Faculty of Medicine
Country United Kingdom 
Sector Academic/University 
PI Contribution Our cell lines remain in great demand and we continue to add new collaborators to our list.
Collaborator Contribution Mutual laboratory visits for training/information and collaborative work. Ongoing research collaboration.Research collaborationOngoing research collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaboration Research collaboration
Impact Publications include PMIDs 20889126, 20375988, 19902259, 19766679, 19737241, 19703278, 19584399, 19553347, 19515812, 19383602, 19233685, 19124603 and all other more recent ones listed under publications. Multidisciplinary including basic laboratory scientists, medically qualified laboratory scientists and pure clinicians.
Start Year 2008
 
Description Numerous research collaborations worldwide 
Organisation Michigan Medicine
Department Department of Internal Medicine
Country United States 
Sector Hospitals 
PI Contribution Our cell lines remain in great demand and we continue to add new collaborators to our list.
Collaborator Contribution Mutual laboratory visits for training/information and collaborative work. Ongoing research collaboration.Research collaborationOngoing research collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaboration Research collaboration
Impact Publications include PMIDs 20889126, 20375988, 19902259, 19766679, 19737241, 19703278, 19584399, 19553347, 19515812, 19383602, 19233685, 19124603 and all other more recent ones listed under publications. Multidisciplinary including basic laboratory scientists, medically qualified laboratory scientists and pure clinicians.
Start Year 2008
 
Description Numerous research collaborations worldwide 
Organisation Mount Sinai Hospital (Canada)
Department Samuel Lunenfeld Research Institute
Country Canada 
Sector Academic/University 
PI Contribution Our cell lines remain in great demand and we continue to add new collaborators to our list.
Collaborator Contribution Mutual laboratory visits for training/information and collaborative work. Ongoing research collaboration.Research collaborationOngoing research collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaboration Research collaboration
Impact Publications include PMIDs 20889126, 20375988, 19902259, 19766679, 19737241, 19703278, 19584399, 19553347, 19515812, 19383602, 19233685, 19124603 and all other more recent ones listed under publications. Multidisciplinary including basic laboratory scientists, medically qualified laboratory scientists and pure clinicians.
Start Year 2008
 
Description Numerous research collaborations worldwide 
Organisation National Institute of Health and Medical Research (INSERM)
Department UMRS 872 (Laboratory of therapeutic innovations & ocular physiopathology)
Country France 
Sector Public 
PI Contribution Our cell lines remain in great demand and we continue to add new collaborators to our list.
Collaborator Contribution Mutual laboratory visits for training/information and collaborative work. Ongoing research collaboration.Research collaborationOngoing research collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaboration Research collaboration
Impact Publications include PMIDs 20889126, 20375988, 19902259, 19766679, 19737241, 19703278, 19584399, 19553347, 19515812, 19383602, 19233685, 19124603 and all other more recent ones listed under publications. Multidisciplinary including basic laboratory scientists, medically qualified laboratory scientists and pure clinicians.
Start Year 2008
 
Description Numerous research collaborations worldwide 
Organisation North Shore Long Island Jewish Medical Center
Department Division of Kidney Diseases and Hypertension
Country United States 
Sector Academic/University 
PI Contribution Our cell lines remain in great demand and we continue to add new collaborators to our list.
Collaborator Contribution Mutual laboratory visits for training/information and collaborative work. Ongoing research collaboration.Research collaborationOngoing research collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaboration Research collaboration
Impact Publications include PMIDs 20889126, 20375988, 19902259, 19766679, 19737241, 19703278, 19584399, 19553347, 19515812, 19383602, 19233685, 19124603 and all other more recent ones listed under publications. Multidisciplinary including basic laboratory scientists, medically qualified laboratory scientists and pure clinicians.
Start Year 2008
 
Description Numerous research collaborations worldwide 
Organisation North Shore Long Island Jewish Medical Center
Department Feinstein Institute for Medical Research
Country United States 
Sector Academic/University 
PI Contribution Our cell lines remain in great demand and we continue to add new collaborators to our list.
Collaborator Contribution Mutual laboratory visits for training/information and collaborative work. Ongoing research collaboration.Research collaborationOngoing research collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaboration Research collaboration
Impact Publications include PMIDs 20889126, 20375988, 19902259, 19766679, 19737241, 19703278, 19584399, 19553347, 19515812, 19383602, 19233685, 19124603 and all other more recent ones listed under publications. Multidisciplinary including basic laboratory scientists, medically qualified laboratory scientists and pure clinicians.
Start Year 2008
 
Description Numerous research collaborations worldwide 
Organisation Radboud University Nijmegen Medical Center
Country Netherlands 
Sector Academic/University 
PI Contribution Our cell lines remain in great demand and we continue to add new collaborators to our list.
Collaborator Contribution Mutual laboratory visits for training/information and collaborative work. Ongoing research collaboration.Research collaborationOngoing research collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaboration Research collaboration
Impact Publications include PMIDs 20889126, 20375988, 19902259, 19766679, 19737241, 19703278, 19584399, 19553347, 19515812, 19383602, 19233685, 19124603 and all other more recent ones listed under publications. Multidisciplinary including basic laboratory scientists, medically qualified laboratory scientists and pure clinicians.
Start Year 2008
 
Description Numerous research collaborations worldwide 
Organisation University of Groningen
Country Netherlands 
Sector Academic/University 
PI Contribution Our cell lines remain in great demand and we continue to add new collaborators to our list.
Collaborator Contribution Mutual laboratory visits for training/information and collaborative work. Ongoing research collaboration.Research collaborationOngoing research collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaboration Research collaboration
Impact Publications include PMIDs 20889126, 20375988, 19902259, 19766679, 19737241, 19703278, 19584399, 19553347, 19515812, 19383602, 19233685, 19124603 and all other more recent ones listed under publications. Multidisciplinary including basic laboratory scientists, medically qualified laboratory scientists and pure clinicians.
Start Year 2008
 
Description Numerous research collaborations worldwide 
Organisation University of Helsinki
Country Finland 
Sector Academic/University 
PI Contribution Our cell lines remain in great demand and we continue to add new collaborators to our list.
Collaborator Contribution Mutual laboratory visits for training/information and collaborative work. Ongoing research collaboration.Research collaborationOngoing research collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaboration Research collaboration
Impact Publications include PMIDs 20889126, 20375988, 19902259, 19766679, 19737241, 19703278, 19584399, 19553347, 19515812, 19383602, 19233685, 19124603 and all other more recent ones listed under publications. Multidisciplinary including basic laboratory scientists, medically qualified laboratory scientists and pure clinicians.
Start Year 2008
 
Description Numerous research collaborations worldwide 
Organisation University of Maryland
Country United States 
Sector Academic/University 
PI Contribution Our cell lines remain in great demand and we continue to add new collaborators to our list.
Collaborator Contribution Mutual laboratory visits for training/information and collaborative work. Ongoing research collaboration.Research collaborationOngoing research collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaborationResearch collaboration Research collaboration
Impact Publications include PMIDs 20889126, 20375988, 19902259, 19766679, 19737241, 19703278, 19584399, 19553347, 19515812, 19383602, 19233685, 19124603 and all other more recent ones listed under publications. Multidisciplinary including basic laboratory scientists, medically qualified laboratory scientists and pure clinicians.
Start Year 2008
 
Description Kidney patient conference 
Form Of Engagement Activity A talk or presentation
Part Of Official Scheme? No
Primary Audience Public/other audiences
Results and Impact Invitation to speak at national conference of kidney patient association on topic of research into nephrotic syndrome; linked with presentation by mother of a child whose life has been devastated by nephrotic syndrome.

Patient awareness of research in the field.
Year(s) Of Engagement Activity 2009