Regulation of glomerular permeability by VEGF

End stage kidney failure is becoming increasingly common across the developed world - averaging a 5% increase per year in the UK. The 37,500 UK patients with end stage kidney disease represent a significant financial burden, representing 3% of the entire health budget consumed by 0.06% of the population. Many kidney diseases stem from injury to the kidney filters or glomeruli. In health these filtering units are very permeable to water and small molecules (promoting the production of urine) but have a low permeability to proteins (which are important molecules to conserve). Thus the filters have a differential permeability to different substances. Many kidney diseases are characterised by a derangement in permeability and leakage of protein into the urine. Furthermore, for reasons that are not clear, the presence of protein in the urine has also recently been identified as a very strong predictor of cardiovascular disease (stokes, heart attacks etc). The glomeruli contains cells (podocytes) that produce molecules such as Vascular Endothelial Growth Factors (VEGF) that regulate glomerular function. We intend to study the effects of two forms of VEGF - VEGF165 and VEGF165b in models of disease in which expression of these molecules may be controlled. Furthermore, since structure predicts function, we will reconstruct these glomeruli in 3D at the electron microscope level.
This study may allow the development of novel strategies to maintain normal or re-establish normal permeability. This may therefore have profound implications not only for kidney patients but also those at risk of cardiovascular disease producing significant financial benefits for health service providers.

Proteinuria is a cardinal feature of glomerular disease. Glomerular disease commonly leads to end stage renal failure, which in turn is associated with reduced longevity (overall 5 year survival on dialysis = 50%, 10% if also diabetic, UK Renal Registry Figures) and increased morbidity. Furthermore, the presence of protein in the urine is a strong predictor of cardiovascular risk in the general population, even in those individuals who have high normo-albuminuric levels. This project will attempt to define the molecular basis for deranged glomerular permeability using a unique combination of resources and skills. The two permeability parameters: hydraulic conductivity (convective permeability to water) and reflection co-efficient (macromolecular selectivity) will be investigated in glomeruli from established transgenic animals with inducible manipulation of 2 podocyte derived molecules known to influence permeability in other vascular beds. These are the angiogenic and anti-angiogenic vascular endothelial growth factor isoforms. In addition, to relate structure to function, the glomerular filtration barrier region (including the recently identified sub-podocyte and interpodocyte spaces) from the same glomeruli from which the physiological parameters have been defined, will be reconstructed in three dimensions at the ultrastructural level.
The combination of these highly specialised resources and skills is unrivalled worldwide and will provide a unique opportunity to elucidate the factors that influence glomerular permeability.
This project may allow the development of novel strategies to maintain or re-establish normal glomerular permeability. Our findings may therefore have profound implications, not only for renal patients and those at risk of cardiovascular disease, but also for the financial drain on health service providers.