부산대학교 도서관

Nephrotic syndrome (NS) is a glomerular disease that is characterized by heavy proteinuria that is associated with edema, hyperlipidemia, and hypertension. Understanding of the pathogenesis of nephrotic syndrome has proved difficult to date and although there have been significant advances, the underlying mechanism is still unknown. One theory to explain the pathogenesis of idiopathic nephrotic syndrome is immune system dysregulation. It is thought that a deleterious circulating factor or factors produced by immune cells act on the glomerular podocyte causing disease. The aim of this work is following up on the immune dysregulation theory to explore potential factor(s) behind nephrotic syndrome. There is growing evidence that the circulating factor that signals deleteriously to the podocyte does so via protease activated receptor 1 (PAR-1) to cause glomerular damage. Complement system involvement in idiopathic nephrotic syndrome has already been demonstrate and interestingly a recent study has shown that the complement factor C4a can increase endothelial cell permeability via PAR-1 which thus made it a target for this study. Adaptive immune system involvement in the syndrome has been demonstrated too, with a study proving supernatant from Th17 cells can modify the actin cytoskeleton of the podocyte and increase its motility making this cell a target for this study too. This thesis consists of two parts: 1 - Determine the effect on glomerular cells of two proteins, neuromedin U and chemokine ligand 20, which were identified during this work as being produced by a steroid resistant Th17 population (adaptive immune system). These proteins are shown to affect podocyte motility and detachment ability that are indicative of changes to the podocyte actin cytoskeleton. 2 - Study the effect of C3a and C4a, two proteins that are part of the innate immune system and known to be linked to kidney disease, on podocytes and glomerular endothelial cells. We show that both C3a and C4a change the phosphorylation of VASP, ERK1/2 and Jnk pathways in both podocytes and glomerular endothelial cells suggesting that these proteins have direct effects on the glomerular cells. Thus, this thesis work has identified four novel proteins that act directly on the podocyte cells of the kidney and which may be involved in the pathogenesis of nephrotic syndrome.