Is Diabetic Nephropathy the Result of a Podocyte Tauopathy?

Diabetic kidney disease (DKD) is the leading cause of kidney failure in the world and increasing at alarming rates due to the diabetes-inducing lifestyles we live. Currently the treatments for DKD are inadequate with many diabetic patients developing kidney failure needing dialysis or a kidney transplant. These patients are also more likely to suffer from cardiovascular problems such as heart attacks and strokes and to die early.

It is also known that being diabetic and/or having kidney disease significantly increases the risk of developing dementia. We have evidence that this link may be due to accumulation of a protein called Tau in the cells of the brain and also in a key kidney cell called the podocyte. In this project we will investigate the importance of having too much "activated Tau" in the podocyte in diabetic and non-diabetic conditions. If we find this is an important factor that damages the kidney it will lead to the development of new types of drugs to prevent cellular Tau accumulation which will hopefully stop diabetic patients from developing kidney failure and the other associated severe problems.

Diabetic Nephropathy (DN) is the leading cause of kidney failure in the world. Its natural history is dominated by progressive albuminuria suggesting that the glomerular podocyte may be an early target cell in this condition. We have evidence that accumulation and phosphorylation of microtubular associated protein Tau (MAPT) occurs in podocytes rendered diabetic. We believe this may be an important early initiator in the pathogenesis of DN and also be a mechanistic explanation as to why patients with diabetes and/or proteinuric kidney disease are significantly more likely to develop Alzheimer's dementia. We hypothesize that in diabetes hyperphosphorylated MAPT accumulates in the podocyte causing cellular dysfunction initiating kidney disease.

To address this hypothesis we have 3 aims to:

1. Define the physiological importance of increased human MAPT in the podocyte in the perfused glomerulus. This will be achieved by generating a podocyte specific human MAPT over expressing mouse model, which will be compared with an MAPT knockout mouse in diabetic and non-diabetic conditions.
2. Assess the molecular actions of MAPT in the human podocyte. MAPT over expressing, wild-type and knockout cell lines will be generated and an array of cellular functions assessed in diabetic and non-diabetic conditions.
3. Define the importance of MAPT hyper-phosphorylation for podocyte function in diabetic and non-diabetic conditions. This will be achieved by using a set of constitutively phospho-active and phospho-null MAPT constructs stably transfected into human podocytes.

Collectively this project will define if podocyte MAPT levels and its phosphorylation status are important in the pathogenesis of DN. If true it will open up many new therapeutic avenues for this condition.

We identify the following groups as likely beneficiaries from work conducted during this project:

1) Patients with Diabetic Nephropathy and Dementia:

If our hypothesis is true it will reveal a new detrimental pathway that could be therapeutically manipulated in the future to prevent podocyte dysfunction and the development of diabetic kidney disease. We would envisage through the development of therapies that either prevent the accumulation and phosphorylation or increase the breakdown of MAPT this could be possible. Full clinical development of new agents is expected to take 10-15 years. However, it may also be possible to repurpose drugs that have already been fully tested and discovered to be safe in humans. One possibility may be agents that induce autophagy which may help breakdown and remove MAPT protein complexes. If this was the case new therapies may become available in 5-10 years. Additionally, if new therapies were found to be beneficial in preventing kidney disease it is possible they may also have similar effects in the brain abrogating neuronal MAPT accumulation and prove to be useful in treating Alzheimer's disease. If this was the case it would have massive impact on society.

2) The NHS:

Diabetic complications and kidney disease are major burdens on the NHS consuming lots of time and finance. If we could prevent the development of diabetic nephropathy this would save the NHS millions of pounds that could be used elsewhere in society. Chronic Kidney Disease stages 3 to 5 are estimated to cost the NHS ~£2billion per year. Half this cost is directed toward provision of renal replacement therapy for ~2% of patients and at least a third of these will be diabetic, this equates to a potential cost saving of approximately £340 million per year.

3) The UK pharmaceutical industry and UK economy:

New jobs would be created to pursue the development of novel therapies to target the MAPT pathway. This would bring wealth to the country. Additionally, it would greatly help the UK economy as patients with DN would be able to continue working in society adding to the countries Gross Domestic Product (GDP).

4) The wider scientific community:

This would stimulate the research community to further investigate the roles of MAPT accumulation in the kidney and beyond.