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.

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.

Publications

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Bowen EE (2018) Advances in our understanding of the pathogenesis of hemolytic uremic syndromes. in American journal of physiology. Renal physiology

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Brosius FC (2014) Podocytes, signaling pathways, and vascular factors in diabetic kidney disease. in Advances in chronic kidney disease

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Coward R (2015) Insulin signaling: implications for podocyte biology in diabetic kidney disease. in Current opinion in nephrology and hypertension

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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

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Gnudi L (2016) Diabetic Nephropathy: Perspective on Novel Molecular Mechanisms. in Trends in endocrinology and metabolism: TEM

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Hale LJ (2013) Insulin signalling to the kidney in health and disease. in Clinical science (London, England : 1979)

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Hale LJ (2013) Insulin directly stimulates VEGF-A production in the glomerular podocyte. 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 Academic/University
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)
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)
Organisation Wellcome Trust 
Department Wellcome Trust Bloomsbury Centre
Sector Academic/University
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)
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)
Organisation European Commission 
Department Innovative Medicines Initiative (IMI)
Sector Multiple
Country European Union (EU)
Start 04/2017 
End 08/2021
 
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 Academic/University
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)
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 Public
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)
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 industry 
Organisation Novo Nordisk
Country Denmark 
Sector Public 
PI Contribution Intellectual input in this collaborative project.
Collaborator Contribution Financial support and intellectual input
Impact Only began 2 months ago
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