The podocyte and parietal epithelial cell in proteinuria and glomerulosclerosis.

Abstract

FSGS has become one of the most common glomerular diseases and is characterized by focal and segmental occurrence of lesions. Proteinuria is an important hallmark of glomerular diseases. Based on findings in a mouse model of FSGS we questioned if PECs play a role in human FSGS. Until now epithelial hyperplasia, which can be prominent in FSGS has been attributed to dedifferentiation and proliferation of podocytes. We performed a detailed study of lesions by serial sectioning, marker analysis and three-dimensional reconstruction of glomeruli. Our study demonstrated that the proliferating epithelial cells in FSGS lesions were negative for podocyte and macrophage markers, but stained for PEC markers. Also the staining characteristics of the matrix deposited by these cells was identical to Bowman's capsule. Taken together, these data argue that proliferating epithelial cells in active FSGS lesions are PECs and question the contribution of the socalled 'de-differentiated' podocyte. The concept of the dedifferentiated-proliferating podocyte needs revision. Progressive FSGS will eventually lead to global glomerulosclerosis. Global glomerulosclerosis is often observed in patients with renal disease or patients with nephrosclerosis. Two types of global glomerulosclerosis are described: the obsolescent type and the solidified type. We noticed the presence of abnormal glomeruli in biopsies of children with a recurrent nephrotic syndrome and we have suggested the term involution to describe this process. We have developed a mouse model of glomerular involution. In this model the small glomeruli had the same characteristics as the involuted glomeruli described in children with minimal change disease. Our mouse model will enable us to investigate in more detail the pathogenesis of glomerular involution. We propose a new scheme for the development of FSGS and glomerular involution. We attribute a central role to parietal epithelial cell injury in determining if podocyte injury and proteinuria progress to FSGS or glomerular involution. If confirmed by further studies the PEC might become a new target for therapy.