Insulin signalling to the podocyte; pathological importance and therapeutic potential.

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.

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.

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.