Structure and development of the glomerular capillary wall and basement membrane

Abstract

The renal glomerular epithelium, Bowman's capsule, and tubule originate from a condensate of mesenchymal cells induced to undergo epithelial differentiation by a branch of the uretic bud. These nephrogenic cells aggregate and begin synthesizing the basement membrane molecules collagen type IV, heparan sulfate proteoglycans, and laminin as shown by immunofluorescence microscopy. Soon, the primitive nephron is invaginated by mesenchymal cells that establish the glomerular endothelium. Electron microscopy, metabolic labeling, and immunocytochemical techniques show that the endothelium and epithelium of early stage glomeruli each synthesize a basement membrane that appears to fuse, giving rise to the glomerular basement membrane (GBM). As development progresses, however, bulk GBM biosynthesis by the endothelium greatly diminishes or ceases. In contrast, GBM assembly by the epithelial podocytes continues and segments of new GBM appear beneath developing foot processes. In vivo labeling experiments with anti-laminin antibodies have shown that this new GBM derived from podocytes is subsequently spliced into existing GBM as capillary loop diameters expand. Molecular mechanisms for basement membrane fusion or splicing are not presently known but may involve partial enzymatic digestion and specific binding interactions among GBM components. The developing glomerular capillary wall, which filters plasma from very early stages, becomes decreasingly permeable to perfused macromolecules such as ferritin or immunoglobulin as the glomerulus matures. Evidence from immunolabeling studies showing that some monoclonal IgGs bind to the GBM only at specific developmental stages also indicates that temporal biochemical changes take place during GBM assembly. Such changes could include molecular rearrangement during basement membrane fusion and splicing and/or enzymatic and compositional modifications during maturation of the filtration barrier.