The role of proteinuria and proximal tubular cells in the development of tubulointerstitial inflammation and scarring in the kidney.

Loss of renal function in chronic kidney disease is correlated with interstitial scarring but the mechanism for the development of interstitial pathology in glomerular disease is unknown. Since the quantity of proteinuria, in renal disease, is correlated with the rate of progression of renal failure it has been suggested that proteinuria may be a cause of progression. Proteinuria could have this effect by altering proximal tubular cell biology resulting in inflammation and scarring in the tubulointerstitium. The experiments described in this thesis investigated alterations in the phenotype of proximal tubular cells in culture following exposure to proteins. Growth of proximal tubular cells is known to occur in progressive kidney disease. It was shown that whilst albumin altered the growth of OK cells, the mixture of proteins present in proteinuric urine, at the same total protein concentration, had a more marked effect. This suggested that effects of protein on tubular cell function may not be simply the result of protein per se but that specific proteins have different effects. A cell culture model of human tubular epithelial cells (HTEC) grown on membrane supports was developed. HTEC produced fibronectin, PDGF and MCP-1. Apical exposure of HTEC to serum proteins increased their basolateral secretion of fibronectin, PDGF and MCP-1. There was also increased monolayer permeability and increased lactate dehydrogenase release by HTEC exposed to serum, suggesting toxicity to the cells. The active component of serum was found in a fraction of molecular weight 43-100kD. Although the major proteins in this fraction were albumin and transferrin, these proteins, added alone to the culture medium did not reproduce the effects of serum. These studies demonstrated that serum proteins if present in the glomerular ultrafiltrate could act on proximal tubular cells to alter their phenotype in a way that would promote interstitial inflammation and scarring.