The podocytes, which are endocytic, have long finger-like processes that completely encircle the outer surface of the capillaries (see
Figs. 33.7 33.8A ). The processes of the podocytes interdigitate to cover the basement membrane and are separated by apparent gaps called filtration slits (see
Figs. 33.7 33.8A ). Each filtration slit is bridged by a thin diaphragm that contains pores with a dimension of 40 × 140 Å. The filtration slit diaphragm, which appears as a continuous structure when viewed by electron microscopy (see
Fig. 33.7B ), is composed of several proteins, including nephrin (NPHS1), NEPH-1, and podocin (NPHS2), and intracellular proteins that associate with the slit diaphragm, including α-actinin-4 (ACTN4) and CD2-AP (
Figs. 33.10 33.11 ). Filtration slits, which function primarily as a size-selective filter, minimize the filtration of proteins and macromolecules that cross the basement membrane from entering Bowman’s space. Because both the basement membrane and filtration slits contain negatively charged glycoproteins, some proteins are held back (i.e., not filtered into Bowman’s space) on the basis of size and charge. For molecules with an effective molecular radius between 18 and 42 Å, cationic molecules are filtered more readily than anionic molecules.
Another important component of the renal corpuscle is the mesangium, which consists of mesangial cells and the mesangial matrix (see
Fig. 33.9 ). Mesangial cells, which possess many properties of smooth muscle cells, provide structural support for the glomerular capillaries, secrete extracellular matrix, exhibit phagocytic activity by removing macromolecules from the mesangium, and secrete prostaglandins and proinflammatory cytokines. Because they also contract and are adjacent to glomerular capillaries, mesangial cells may influence GFR by regulating blood flow through the glomerular capillaries or by altering the capillary surface area. Mesangial cells located outside the glomerulus (between the afferent and efferent arterioles) are called extraglomerular mesangial cells.
The nephrotic syndrome is produced by a variety of disorders and is characterized by increased permeability of the glomerular capillaries to proteins and by loss of normal podocyte structure, including effacement (i.e., thinning) of foot processes. The augmented permeability to proteins results in increased urinary protein excretion (proteinuria). Thus the appearance of proteins in urine can indicate kidney disease. Individuals with this syndrome often develop hypoalbuminemia as a result of the proteinuria. In addition, generalized edema is commonly seen in nephrotic individuals. Mutations in several genes encoding either slit diaphragm proteins (see
Figs. 33.10 33.11), including nephrin, NEPH-1, and podocin, or intracellular proteins that functionally interact with slit diaphragm proteins, such as CD2-AP and α-actinin 4 (ACTN4), result in proteinuria and kidney disease. For example, mutations in the nephrin gene (NPHS1) in congenital nephrotic syndrome lead to abnormal or absent slit diaphragms, causing massive proteinuria and renal failure. In addition, mutations in the podocin gene (NPHS2) cause autosomal recessive, steroid-resistant nephrotic syndrome. These naturally occurring mutations and knockout studies in mice demonstrate that nephrin, NEPH-1, podocin, CD2-AP, and α-actinin-4 play key roles in normal glomerular podocyte structure and function.