Building the Glomerulus

he structural integrity of the glomerular capillaries stems from the stereotyped arrangement of the three constituent cell types: Podocytes (also called visceral epithelial cells), endothelial cells, and mesangial cells. The ar- rangement of these cells depends in part on their interactions with extracellular matrix, most notably the glomerular base- ment membrane (GBM). In this essay, I discuss the role of the GBM in glomerulogenesis and in kidney function and disease and provide a historical perspective regarding how our current state of knowledge was achieved. Basement Membranes Basement membranes are thin sheets of specialized extracel- lular matrix found in tissues throughout the body. They under- lie all epithelial and endothelial cells and surround all muscle cells, fat cells, and axons in peripheral nerves. Basement mem- branes have been shown to influence cell proliferation, migra- tion, and differentiation and to be involved in compartmental- ization of tissues and in filtration. All basement membranes contain four major components: Laminin, type IV collagen, nidogen/entactin, and sulfated pro- teoglycans. Each of these components actually describes a fam- ily of individual proteins that are differentially distributed in basement membranes. The initial biochemical studies of these components in the 1970s and 1980s were facilitated by the existence of the Engelbreth-Holm-Swarm (EHS) tumor, a tumor of mouse origin that produces large amounts of particular basement membrane protein isoforms that are easily purified. These isoforms are now known as laminin-1 (Figure 1), collagen IV (1)2(2)1, nidogen-1 or entactin-1, and perlecan. Once these proteins were purified and biochemically charac- terized, they were used as immunogens to develop antibodies for localization in tissues. Because of the abundance of base- ment membranes in the kidney—indeed, each nephron and its attached collecting duct is entirely surrounded by a continuous basement membrane—the kidney was a common site for local- izing basement membrane proteins. Antibodies to most of the EHS proteins stained all kidney basement membranes. How- ever, some but not all laminin antibodies presented interesting exceptions to this.