Filtration slit diaphragm is a complex zipper-like sheet structure formed by a transmembrane protein nephrin. The extracellular domains of nephrins emerge from the opposite foot processes of neighboring podocytes and interdigitate in the center of the slit forming a central density with pores on both sides. The intracellular domains of nephrins interact with actin cytoskeleton within the cytoplasm of foot processes. The sheet of nephrin molecules is reinforced near its attachment to the foot processes by Neph1 and Neph2 proteins that interact with each other and with nephrin. The other adhesion molecules such as P-cadherin, FAT1, and FAT2 are also found in this region. Note that foot processes of podocytes are separated by the glomerular basement membrane (GBM) from fenestrated endothelial cells lining glomerular capillaries. (Redrawn from Tryggvason K, Patrakka J, Wartiovaara J. Hereditary proteinuria syndromes and mechanisms of proteinuria. N Engl J Med 2006;354:1387–401.) podocytes in the areas where the epithelial basement membrane is absent or incomplete (see Fig 20.16).
 Secretion. Mesangial cells synthesize and secrete a variety of molecules such as interleukin 1 (IL-1), PGE2, and platelet-derived growth factor (PDGF), which play a central role in response to glomerular injury.
 Modulation of glomerular distension. Mesangial cells have contractile properties. In the past, it was suggested that contraction of mesangial cells could increase the intraglomerular blood volume and filtration pressure. Recent studies revealed that mesangial contribution to glomerular filtration rate is minimal, and the mesangial cells may function in regulating glomerular distension in response to increased blood pressure.
 Clinically, it has been observed that mesangial cells proliferate in certain kidney diseases, in which abnormal amounts of protein and protein complexes are trapped in the GBM. Proliferation of mesangial cells is a prominent feature in the immunoglobulin A (IgA) nephropathy (Berger disease), membranoproliferative glomerulonephritis, lupus nephritis, and diabetic nephropathy.
FIGURE 20.15 • Immunofuorescent-stained glomerulus.
This triple-exposure micrograph of a normal adult rat glomerulus is immunostained with two different antibodies. One antibody recognizes specific extracellular components, namely, basement membrane heparan sulfate proteoglycan (BM-HSPG, rhodamine label). The other antibody recognizes basement membrane chondroitin sulfate proteoglycan (BM-CSPG, fluorescein label). Because it is a triple-exposure micrograph, a yellow color occurs where the two fluorescent labels exactly codistribute. The blue fluorescence is nuclear counterstaining with Hoechst nuclear stain. The micrograph shows that compartmentalization occurs with respect to glomerular proteoglycan populations. The glomerular capillary basement membrane is composed exclu sively of BM-HSPG, whereas the mesangial matrix (yellow) contains both BM-HSPG and BM-CSPG. Bowman’s capsule appears to be strongly stained by only BM-CSPG antibodies. 360. (Courtesy of Dr. Kevin J. McCarthy.)
Embryologically, mesangial, and juxtaglomerular cells (discussed in a following paragraph) are derived from smooth muscle cell precursors. Although mesangial cells are clearly phagocytotic, they are unusual in the sense that they are not derived from the usual precursor cells of the mononuclear phagocytotic system, the blood-borne monocytes.
The juxtaglomerular apparatus includes the macula densa, the juxtaglomerular cells, and the extraglomerular mesangial cells.