Role of the podocyte (and glomerular endothelium) in building the GBM

Abstract

This article summarizes the basic cellular and extracellular events in the development of the glomerulus and assembly of the glomerular basement membrane (GBM), paying special attention to laminin (LM) and type IV collagen. Cellular receptors for GBM proteins, including the integrins, dystroglycan, and discoidin domain receptor 1 also are discussed. Evidence is reviewed showing that the laminin isoform present in the earliest GBM, LM-111, and final isoform found in the mature GBM, LM-521, are each derived from both endothelial cells and podocytes. Although the early collagen α1α2α1(IV) similarly derives from endothelial cells and podocytes, collagen α3α4α5(IV) found in fully mature GBM is a product solely of podocytes. Genetic diseases affecting laminin and type IV collagen synthesis also are presented, with an emphasis on mutations to LAMB2 (Pierson syndrome) and COL4A3, COL4A4, and COL4A5 (Alport syndrome), and their experimental mouse models. Stress is placed on the assembly of a compositionally correct GBM for the acquisition and maintenance of glomerular barrier properties.

Figure 1

Diagram showing stages of glomerular capillary wall development and cellular origins of different laminin and collagen IV isoforms. A: During vascular cleft and early capillary loop stages, a double basement membrane is located between the endothelium and podocyte and this dual structure fuses. This immature GBM contains LM-111 and collagen α1α2α1(IV), both of which originate in endothelial cells and podocytes. B: During intermediate stages of glomerular development, newly synthesized segments of basement membrane are seen beneath developing podocyte foot processes. LM-521 can now be detected, and originates from both endothelial cells and podocytes. Collagen α3α4α5(IV) is also seen for the first time at this stage, but this isoform derives solely from podocytes. C: As glomeruli mature, the glomerular capillary loops achieve their final dimensions. The GBM contains only LM-521 (derived from endothelial cells and podocytes) and collagen α3α4α5(IV) (derived only from podocytes). Reprinted with permission.

Figure 2

Post-fixation immunoperoxidase electron microscopy of developing mouse glomerular capillary wall using anti-collagen α3α4α5(IV) IgG. Peroxidase reaction product appears within the GBM and intracellular biosynthetic organelles (arrowheads) of podocytes (Po). Labeling is absent in the glomerular endothelium (En). Reprinted with permission.

Figure 3

Section of immature Alport mouse glomerulus double labeled with (A): podocyte-specific anti-GLEPP1 and (B): anti-collagen α5(IV). Merged image (C) shows intracellular immunolabeling for collagen α5(IV) (arrows) exclusively within podocytes. Reprinted with permission.