Insulin signalling to the podocyte; pathological importance and therapeutic potential.
Lead Research Organisation:
University of Bristol
Department Name: Sch of Medical Sciences
Abstract
The number of people in the world who are developing end stage kidney failure is rapidly increasing principally due to this condition being associated with diabetes. When this occurs patients require multiple medications, together with dialysis or kidney transplantation, or they die. Discovering new ways to prevent kidney failure is therefore critical. We have discovered that a cell, called the podocyte, in the kidney is implicated in the early stages of kidney disease (before the kidney completely fails) and this cell is responsive to a hormone called insulin. It appears that this cell needs insulin to remain healthy. We now want to understand exactly how insulin signals to the podocyte and explore if increasing insulin sensitivity of the this cell can prevent the kidney from completely failing. If this is true then strategies that increase podocyte insulin sensitivity could have great therapeutic potential in preventing kidney failure and stopping patients needing dialysis or kidney transplantation.
Technical Summary
The loss of albumin into the urine is called albuminuria and this, if prolonged, results in kidney failure and cardiovascular disease. A key cell in the filtration barrier of the kidney that prevents albuminuria is called the podocyte. We have recently shown that the podocyte is an insulin responsive cell type and that when insulin sensitivity of this cell is lost it results in widespread renal damage. In the pathogenesis of diabetic nephropathy, and indeed all forms of chronic kidney disease (CKD), there is associated cellular insulin resistance which starts early in the process. Diabetic nephropathy is the leading cause of kidney failure in the world.
The aims of this project are to:
(1) Focus on the proximal insulin signalling apparatus in the podocyte to understand the biological roles of the two major receptors through which insulin can signal, the insulin and the IGF-1 receptor, and map the signalling pathways they elicit. The importance of these receptors will be assessed in development and maturity. We will then go on to map the molecular pathways in the glomerulus which these receptors are modulating to understand the mechanisms underlying renal damage that occur when their signalling capabilities are diminished.
(2) Examine if enhancing insulin sensitivity specifically in the podocyte protects against the development of renal failure associated with diabetes mellitus. If true, this has great therapeutic potential.
The aims of this project are to:
(1) Focus on the proximal insulin signalling apparatus in the podocyte to understand the biological roles of the two major receptors through which insulin can signal, the insulin and the IGF-1 receptor, and map the signalling pathways they elicit. The importance of these receptors will be assessed in development and maturity. We will then go on to map the molecular pathways in the glomerulus which these receptors are modulating to understand the mechanisms underlying renal damage that occur when their signalling capabilities are diminished.
(2) Examine if enhancing insulin sensitivity specifically in the podocyte protects against the development of renal failure associated with diabetes mellitus. If true, this has great therapeutic potential.
Planned Impact
Realising the objective of this programme of research will benefit the following groups:
1. Patients with glomerular disease - The main non-academic beneficiaries will be patients with kidney disease, which is an ever-growing scourge in the developed world with major health economic implications. Improved understanding of the causes of proteinuria will lead to the development of new therapeutic targets combating both kidney failure and also associated cardiovascular disease. The likely timescale for this is 10-15 years.
2. The general public. The other non-academic beneficiaries will be the public: I am committed to public engagement and have many years of experiencing of addressing lay groups including patients, carers and the general public. Improved education about the importance of urine testing for protein and screening for hypertension, diabetes and cardiovascular disease will have tangible health benefits in a relatively short timescale, within 1-2 years. I also regularly address medical professionals in East Africa where there is a huge burden of chronic renal disease. Identifying early preventative therapies for these patients is crucial as there is currently very limited provision for dialysis or transplantation here and the majority of patients who proceed into end stage renal failure die.
3. Charities - This research programme will make conceptual changes in several areas of glomerular biology and disease and so influence the direction of future research into avenues following the targets identified. This will allow more efficient use of scarce financial resources spent by charities on research.
4. Clinicians - understanding and developing treatments for patients with kidney diseases, both by identifying targets and subsequent design of clinical trials, will allow clinicians to participate in the scientific advances being made as well as informing patients of new treatment options on the horizon.
5. Academic community- see previous section.
6. Industry - by forming additional partnerships with industrial/pharmaceutical companies we will develop new drug/compound pipelines based on targets that we identify in this programme, thus creating commercial opportunities for a worldwide market.
7. The UK economy. The UK currently has over 40,000 patients on renal replacement therapies, around 700 per million population, total cost over £700 million per year, over 2% of NHS budget being spent on 0.1% of the population. Recent UK government figures show that CKD affects at least 3% of the population. This programme of work will directly address the commonest causes of permanent renal failure including Diabetic nephropathy (DN).
- Among patients starting renal replacement therapy, the incidence of DN doubled from the years 1991-2001
- DN accounts for 30-40% of patients with ESRD, with the incidence increasing year on year, mirroring the current worldwide rise in obesity and type II diabetes.
Through the mechanisms we propose, a target decrease in progression of diseases to ESRD of 30% would save £84M per year, and of just 10% would save £28M per year for the NHS.
1. Patients with glomerular disease - The main non-academic beneficiaries will be patients with kidney disease, which is an ever-growing scourge in the developed world with major health economic implications. Improved understanding of the causes of proteinuria will lead to the development of new therapeutic targets combating both kidney failure and also associated cardiovascular disease. The likely timescale for this is 10-15 years.
2. The general public. The other non-academic beneficiaries will be the public: I am committed to public engagement and have many years of experiencing of addressing lay groups including patients, carers and the general public. Improved education about the importance of urine testing for protein and screening for hypertension, diabetes and cardiovascular disease will have tangible health benefits in a relatively short timescale, within 1-2 years. I also regularly address medical professionals in East Africa where there is a huge burden of chronic renal disease. Identifying early preventative therapies for these patients is crucial as there is currently very limited provision for dialysis or transplantation here and the majority of patients who proceed into end stage renal failure die.
3. Charities - This research programme will make conceptual changes in several areas of glomerular biology and disease and so influence the direction of future research into avenues following the targets identified. This will allow more efficient use of scarce financial resources spent by charities on research.
4. Clinicians - understanding and developing treatments for patients with kidney diseases, both by identifying targets and subsequent design of clinical trials, will allow clinicians to participate in the scientific advances being made as well as informing patients of new treatment options on the horizon.
5. Academic community- see previous section.
6. Industry - by forming additional partnerships with industrial/pharmaceutical companies we will develop new drug/compound pipelines based on targets that we identify in this programme, thus creating commercial opportunities for a worldwide market.
7. The UK economy. The UK currently has over 40,000 patients on renal replacement therapies, around 700 per million population, total cost over £700 million per year, over 2% of NHS budget being spent on 0.1% of the population. Recent UK government figures show that CKD affects at least 3% of the population. This programme of work will directly address the commonest causes of permanent renal failure including Diabetic nephropathy (DN).
- Among patients starting renal replacement therapy, the incidence of DN doubled from the years 1991-2001
- DN accounts for 30-40% of patients with ESRD, with the incidence increasing year on year, mirroring the current worldwide rise in obesity and type II diabetes.
Through the mechanisms we propose, a target decrease in progression of diseases to ESRD of 30% would save £84M per year, and of just 10% would save £28M per year for the NHS.
People |
ORCID iD |
Richard Coward (Principal Investigator / Fellow) |
Publications
Barreiro K
(2023)
An in vitro approach to understand contribution of kidney cells to human urinary extracellular vesicles
in Journal of Extracellular Vesicles
Beal F
(2023)
How to solve a clinical conundrum: Have you tried a trio exome analysis?
in Archives of disease in childhood - Education & practice edition
Bowen EE
(2018)
Advances in our understanding of the pathogenesis of hemolytic uremic syndromes.
in American journal of physiology. Renal physiology
Brosius FC
(2014)
Podocytes, signaling pathways, and vascular factors in diabetic kidney disease.
in Advances in chronic kidney disease
Butler MJ
(2019)
Aldosterone induces albuminuria via matrix metalloproteinase-dependent damage of the endothelial glycocalyx.
in Kidney international
Carrasco AG
(2023)
The protective role of peroxisome proliferator-activated receptor gamma in lipotoxic podocytes.
in Biochimica et biophysica acta. Molecular and cell biology of lipids
Coward R
(2015)
Insulin signaling: implications for podocyte biology in diabetic kidney disease.
in Current opinion in nephrology and hypertension
Ding M
(2013)
Regulation of hypoxia-inducible factor 2-a is essential for integrity of the glomerular barrier.
in American journal of physiology. Renal physiology
Ding WY
(2014)
Initial steroid sensitivity in children with steroid-resistant nephrotic syndrome predicts post-transplant recurrence.
in Journal of the American Society of Nephrology : JASN
Garner KL
(2018)
Enhanced insulin receptor, but not PI3K, signalling protects podocytes from ER stress.
in Scientific reports
Gnudi L
(2016)
Diabetic Nephropathy: Perspective on Novel Molecular Mechanisms.
in Trends in endocrinology and metabolism: TEM
Hale LJ
(2013)
The insulin receptor and the kidney.
in Current opinion in nephrology and hypertension
Hale LJ
(2013)
Insulin signalling to the kidney in health and disease.
in Clinical science (London, England : 1979)
Hale LJ
(2013)
Insulin-like growth factor-II is produced by, signals to and is an important survival factor for the mature podocyte in man and mouse.
in The Journal of pathology
Hale LJ
(2013)
Insulin directly stimulates VEGF-A production in the glomerular podocyte.
in American journal of physiology. Renal physiology
Hartley PS
(2020)
Modeling Podocyte Biology Using Drosophila Nephrocytes.
in Methods in molecular biology (Clifton, N.J.)
Holme A
(2013)
Glomerular involvement in the arthrogryposis, renal dysfunction and cholestasis syndrome.
in Clinical kidney journal
Hosawi SB
(2020)
Global proteomic analysis of insulin receptor interactors in glomerular podocytes.
in Wellcome open research
Hunter R
(2021)
Extracellular RNA moves from the glomerulus to the renal tubule
Hurcombe JA
(2019)
Podocyte GSK3a is important for autophagy and its loss detrimental for glomerular function.
in FASEB bioAdvances
Hurcombe JA
(2019)
Podocyte GSK3 is an evolutionarily conserved critical regulator of kidney function.
in Nature communications
Jackson L
(2018)
The molecular biology of pelvi-ureteric junction obstruction.
in Pediatric nephrology (Berlin, Germany)
Karet Frankl FE
(2016)
UK Renal Research Strategy
Keir LS
(2017)
VEGF regulates local inhibitory complement proteins in the eye and kidney.
in The Journal of clinical investigation
Lay A
(2014)
Recent advances in our understanding of insulin signalling to the podocyte.
in Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
Lay AC
(2018)
The Evolving Importance of Insulin Signaling in Podocyte Health and Disease.
in Frontiers in endocrinology
Lay AC
(2020)
An In Vitro Method to Analyze Glucose Uptake in Podocytes.
in Methods in molecular biology (Clifton, N.J.)
Lay AC
(2020)
A role for NPY-NPY2R signaling in albuminuric kidney disease.
in Proceedings of the National Academy of Sciences of the United States of America
Marlais M
(2014)
Genetics and the nephron.
in Archives of disease in childhood. Education and practice edition
Marlais M
(2015)
Paediatrics, insulin resistance and the kidney.
in Pediatric nephrology (Berlin, Germany)
Moore SF
(2015)
Loss of the insulin receptor in murine megakaryocytes/platelets causes thrombocytosis and alterations in IGF signalling.
in Cardiovascular research
Mühlig AK
(2020)
Podocytes Produce and Secrete Functional Complement C3 and Complement Factor H.
in Frontiers in immunology
Oltean S
(2017)
Diabetic Nephropathy: Novel Molecular Mechanisms and Therapeutic Avenues
in BioMed Research International
Platt C
(2017)
Peroxisome proliferator activating receptor-? and the podocyte.
in Nephrology, dialysis, transplantation : official publication of the European Dialysis and Transplant Association - European Renal Association
Pope RJ
(2020)
An information theoretic approach to insulin sensing by human kidney podocytes.
in Molecular and cellular endocrinology
Ramnath R
(2014)
Matrix metalloproteinase 9-mediated shedding of syndecan 4 in response to tumor necrosis factor a: a contributor to endothelial cell glycocalyx dysfunction.
in FASEB journal : official publication of the Federation of American Societies for Experimental Biology
Ramnath Raina D.
(2020)
Blocking matrix metalloproteinase-mediated syndecan-4 shedding restores the endothelial glycocalyx and glomerular fi ltration barrier function in early diabetic kidney disease
in KIDNEY INTERNATIONAL
Rhodes HL
(2015)
Clinical and genetic analysis of patients with cystinuria in the United Kingdom.
in Clinical journal of the American Society of Nephrology : CJASN
Santamaria B
(2015)
IRS2 and PTEN are key molecules in controlling insulin sensitivity in podocytes.
in Biochimica et biophysica acta
Tse Y
(2018)
Preserving oral history: 50 years of paediatric nephrology in Europe.
in Archives of disease in childhood
Wonnacott A
(2022)
MicroRNAs and their delivery in diabetic fibrosis
in Advanced Drug Delivery Reviews
Ziauddeen N
(2023)
Role of foetal kidney size on kidney function in childhood: the born in bradford cohort renal study.
in BMC nephrology
Østergaard MV
(2017)
DBA2J db/db mice are susceptible to early albuminuria and glomerulosclerosis that correlate with systemic insulin resistance.
in American journal of physiology. Renal physiology
Description | "Aldosterone-induced endothelial glycocalyx dysfunction, a potential therapeutic target in proteinuria?" MRC clinical PhD Fellowship |
Amount | £234,000 (GBP) |
Funding ID | MR/M018237/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 10/2015 |
End | 10/2018 |
Description | "Investigating adeno- associated virus as a vector for gene therapy in steroid resistant nephrotic syndrome" Kidney Research UK Clinical Fellowship |
Amount | £186,000 (GBP) |
Funding ID | TF7/2015 |
Organisation | Kidney Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2016 |
End | 01/2019 |
Description | "MicroRNA regulation of insulin signalling in the podocyte" Clinical PhD project |
Amount | £209,000 (GBP) |
Funding ID | 105728/Z/14/Z |
Organisation | Wellcome Trust |
Department | Wellcome Trust Bloomsbury Centre |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 10/2016 |
End | 10/2019 |
Description | "Using the fruit fly Drosophila to understand podocyte biology in diabetic nephropathy - a pilot study" Kidney Research UK innovation grant |
Amount | £36,000 (GBP) |
Funding ID | IN10/2015 |
Organisation | Kidney Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 10/2016 |
End | 10/2017 |
Description | Clinical PhD Studentship examining Shiga toxin HUS |
Amount | £221,000 (GBP) |
Organisation | Kidney Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 10/2016 |
End | 10/2019 |
Description | Clinical Primer |
Amount | £31,988 (GBP) |
Organisation | Wellcome Trust |
Department | Wellcome Trust Institutional Strategic Support Fund |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2014 |
End | 07/2015 |
Description | Developing a high throughput assay to study cystinuric kidney disease |
Amount | £66,000 (GBP) |
Organisation | Kidney Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 04/2017 |
End | 04/2018 |
Description | European Union IMI grant "BEAt DKD" |
Amount | € 29,000,000 (EUR) |
Funding ID | 115974 |
Organisation | European Commission |
Department | Innovative Medicines Initiative (IMI) |
Sector | Public |
Country | Belgium |
Start | 04/2017 |
End | 08/2021 |
Description | Identifying New Molecular Pathways and Therapeutic Targets in Diabetic Kidney Disease- PSMB project grant |
Amount | £1,003,983 (GBP) |
Funding ID | MR/W019582/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 03/2022 |
End | 02/2026 |
Description | KRUK Medical Student Fellowship- Developing a human cystinuria proximal tubular cell model |
Amount | £5,000 (GBP) |
Organisation | Kidney Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 10/2016 |
End | 06/2017 |
Description | KRUK clinical PhD Fellowship |
Amount | £168,000 (GBP) |
Organisation | Kidney Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 05/2012 |
End | 11/2014 |
Description | KRUK project grant |
Amount | £196,588 (GBP) |
Organisation | Kidney Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2012 |
End | 09/2015 |
Description | Kidney Research UK project grant |
Amount | £156,748 (GBP) |
Organisation | Kidney Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 09/2014 |
End | 04/2017 |
Description | MRC PSMB project grant (co-applicant) for Signalling pathways to proteinuria - part II. Establishment of b3 integrin and TRPC6 as tractable renal disease targets |
Amount | £624,810 (GBP) |
Funding ID | MR/R003017/1 |
Organisation | Medical Research Council (MRC) |
Sector | Public |
Country | United Kingdom |
Start | 09/2017 |
End | 09/2020 |
Description | Medical Student Research bursary- Identifying key insulin signalling pathways in the podocyte |
Amount | £5,000 (GBP) |
Organisation | Kidney Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 10/2016 |
End | 05/2017 |
Description | Medical student Inspire grant |
Amount | £1,000 (GBP) |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 06/2015 |
End | 07/2015 |
Description | Message in a bottle: signalling from glomerulus to renal tubule via RNA in extracellular vesicles- I am a sponsor on this for Dr Rob Hunter |
Amount | £472,987 (GBP) |
Funding ID | 209562 |
Organisation | Wellcome Trust |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 01/2018 |
End | 01/2021 |
Description | Science-Industry grant |
Amount | £200,000 (GBP) |
Organisation | Novo Nordisk |
Sector | Private |
Country | Denmark |
Start | 04/2014 |
End | 04/2016 |
Description | Student KRUK MSc research bursary |
Amount | £5,000 (GBP) |
Organisation | Kidney Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 10/2015 |
End | 06/2016 |
Description | Takeda scientific industry grant |
Amount | £220,000 (GBP) |
Organisation | Takeda Cambridge Ltd |
Sector | Private |
Country | United Kingdom |
Start | 08/2015 |
End | 08/2017 |
Description | Targeting glomerular insulin signalling to treat diabetic kidney disease: an information theoretic approach. |
Amount | £200,000 (GBP) |
Funding ID | RP_024_20170302 |
Organisation | Kidney Research UK |
Sector | Charity/Non Profit |
Country | United Kingdom |
Start | 03/2018 |
End | 03/2021 |
Description | Co lead of work package for IMI European Union project |
Organisation | European Union |
Country | European Union (EU) |
Sector | Public |
PI Contribution | We are part of a major European Union directive to study diabetic kidney disease. I am co lead for the Experimental medicine arm of this project. |
Collaborator Contribution | Multiple industrial partners are involved in this project. |
Impact | Just started! |
Start Year | 2017 |
Description | Post-doctoral Research Fellow sponsored by Novo Nordisk |
Organisation | Novo Nordisk |
Country | Denmark |
Sector | Private |
PI Contribution | Intellectual input in this collaborative project. |
Collaborator Contribution | Financial support and intellectual input |
Impact | American Society of Physiology publication describing a new mouse model of Diabetic Nephropathy. PMID: 27852608 |
Start Year | 2014 |
Description | Takeda industry academic collaboration |
Organisation | Takeda Cambridge Ltd |
Country | United Kingdom |
Sector | Private |
PI Contribution | This is a post-doctoral 2 year project funded by Takeda to study podocyte biology in insulin resistance in relation to ER stress. |
Collaborator Contribution | This is a collaborative project with intellectual input from both parties. |
Impact | Only 6 months old. |
Start Year | 2016 |
Description | Asked to speak on Radio 5 live about kidney stones |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | Highlighting that kidney disease and kidney stones are an issue for the general public and that more research needs to be performed to understand them in more detail. |
Year(s) Of Engagement Activity | 2016 |
Description | University Press release and local media interest in Collaborative European grant investigating diabetic kidney disease |
Form Of Engagement Activity | A press release, press conference or response to a media enquiry/interview |
Part Of Official Scheme? | No |
Geographic Reach | National |
Primary Audience | Media (as a channel to the public) |
Results and Impact | The university produced a Press release about the recent Collaborative European grant investigating biomarkers associated with diabetic kidney disease. |
Year(s) Of Engagement Activity | 2017 |
URL | http://www.bristol.ac.uk/news/2017/february/beat-dkd.html |