The glomeruli of kidney are selective filtering corpuscles composed of a capillary network, podocytes, and mesangial cells (panel A). The glomerular basement membrane (GBM) is situated between capillary endothelia and podocytes (cf. Fig. 107). All three cell types and the GBM are important for the ultrafiltration of plasma. The fenestrated endothelia (arrowheads in panel B) face the blood and differ from other fenestrated endothelia (cf. Fig. 148), with their larger size of pores and lack of diaphragms. The podocytes protrude in the urinary space (US) and their peculiar shape is best appreciated by scanning electron microscopy (panel C). From their cell body, long ramifications originate, the primary processes, which embrace the capillaries. From them, interdigitating secondary processes originate, the foot processes, which form the narrow filtration slits (30–40 nm wide) that are bridged by slit diaphragms (arrows in panel B). Slit diaphragms resemble adherens intercellular junctions and mark the border between the apical and basal podocyte plasma membrane. The foot process base inserts into the GBM. The transmembrane proteins podocalyxin and podoplanin as well as the podocyte-associated talin 1 are important for the shape of podocytes.

Podocytes possess a glycocalyx rich in negatively charged sialic acids, the glomerular epithelial polyanion, which is formed mainly by podocalyxin. The filtration slits stay open by repulsion through negatively charged sialic acids of podocalyxin, which acts as an antiadhesin. Nephrin, which belongs to the immunoglobulin superfamily of adhesion molecules, is found exclusively in the slit diaphragm and is an important component of an isoporous zipper-like filter structure. Nephrin is linked to the cytoskeleton through ezrin.

Accordingly, the filtration machinery is constituted by endothelia, the highly hydrated GBM, and the diaphragms bridging the filtration slits. Podocalyxin, nephrin, podocin, and CD2-AP represent its main molecular components in addition to negatively charged GBM components. The filter is highly permeable for water, and only the slit diaphragm poses a barrier. The negative charges of endothelia and the GBM are important to filter macromolecules according to their charge, whereas the selection according to molecular mass and configuration occurs in the GBM and at the level of the slit diaphragms. Through their endocytotic activities, podocytes and mesangial cells contribute to the functional maintenance of the glomerular filter by removing escaped proteins from the slit diaphragms and from the subendothelial space. RBC: red blood cells.

The impairment of the glomerular filter occurring in various acquired and inherited diseases results in nephrotic syndrome, characterized by proteinuria, edema, hypoalbuminemia, and hyperlipidemia. In minimal change glomerulopathy, diffuse effacement of podocyte foot processes (panels A and B), absence of slit diaphragms (arrows in panel B), lipid droplets in podocytes (asterisks in panel B), and microvilli hypertrophy (arrowheads in panels A and B) are observed. Podocyte detachment from the glomerular basement membrane (GBM) may occur. Protein reabsorption by proximal tubular epithelia results in cytoplasmic protein-filled vacuoles (open asterisks in panel C). In puromycin-induced nephrotic syndrome, a rat model of human minimal change glomerulopathy, reduced sialylation of podocalyxin, and downregulation of podoplanin was observed. Genetic ablation of sialic acid synthesis recapitulated the morphology of minimal change glomerulopathy, including reduced sialylation of podocalyxin.

Various congenital nephrotic syndromes result in similar fine structural changes, and few of the causative genes have been identified. The congenital nephrotic syndrome of the Finnish type is the result of mutations of the NPHS1 gene coding for nephrin. In a less severe, steroid-resistant, familial nephrotic syndrome, the causative gene, NPHS2, was mapped and identified to encode for podocin. These pathological conditions show the importance of nephrin and podocin in normal glomerular filtration.

An immunoglobulin superfamily protein, the CD2-associated protein (CD2-AP), known to be involved in contact stabilization between T cells and antigen-presenting cells, has been shown to cause a congenital nephrotic syndrome in mice that are deficient in CD2-AP. In normal mice, CD2-AP is expressed in podocytes and associated with nephrin present in the slit diaphragm.