In health, only tiny amounts of protein are excreted in the urine. Loss of even very small amounts of albumin (microalbuminuria) has major health and wealth implications, being a powerful independent marker of cardiovascular risk. Loss of larger amounts of albumin is a cardinal feature of kidney disease and a potent risk factor for progressive loss of kidney function. Albuminuria is a major global healthcare issue as it is commonly a prelude to ESRF and is independently linked to cardiovascular disease, in both diabetic and non-diabetic subjects. Of the 37,000 patients on renal replacement in the UK albuminuria will have a significant role in disease progression in approximately 60%. The annual cost of dialysis alone worldwide is in excess of £55 billion. Prevention of albuminuria is achieved by the glomerular filtration barrier (GFB) which is a specialised sieve found in the glomerulus of the kidney. It allows small molecules and water to freely pass from the blood into the urine but prevents larger molecules such as albumin entering the urine.
Our focus is to understand the mechanisms whereby proteinuria is prevented in the healthy situation, with a focus on the two highly specialised cell types that make up the filtration barrier in the glomerulus; the glomerular epithelial cell or podocyte and the glomerular endothelial cell (GEnC) that lines the glomerular capillary wall, how they communicate with eachother and how this may change in disease.
We have developed unique conditionally immortalised human podocyte cell lines including wild-type cells, now the gold standard tool for study of this specialized cell and a range of lines derived from children with podocyte specific gene defects. This range of ‘natural human knockout’ cell lines is an exceptional resource for studying aspects of podocyte function and disease We also have unique human GEnC derived using similar conditional immortalisation technology. Our work is translated from in vitro to in vivo using sophisticated transgenic mouse models targeting the specific expression/knockdown of proteins in the podocyte using Cre recombinase or Tetracycline technologies.