Podocyte foot processes anatomy is depicted in Figure 33.10. The figure illustrates the proteins that form the slit diaphragm between adjacent foot processes. Nephrin and NEPH1 are membrane-spanning proteins that interact through their large extracellular domains. Podocin, also a membrane-spanning protein, organizes nephrin and NEPH1 in specific microdomains in the plasma membrane. This organization is crucial for signaling events that determine the structural integrity of podocyte foot processes. Many proteins in the slit diaphragm interact with adapter proteins inside the cell, including CD2-AP. Adapter proteins bind to the filamentous actin (F-actin) cytoskeleton, which, in turn, binds to proteins such as α3β1 and MAGI-1. These proteins interact with proteins expressed by the glomerular basement membrane (GBM). Other proteins mentioned in the figure include α-act-4, α-actinin 4; α3β1, α3β1 integrin; α-DG, α-dystroglycan; FAT, a protocadherin; MAGI-1, a membrane-associated guanylate kinase protein; NHERF-2, Na+-H+ exchanger regulatory factor 2; P, paxillin; P-Cad, P-cadherin; Synpo, synaptopodin; T, talin; V, vinculin; Z, zona occludens. Mesangial cells play a role in the development of immune complex–mediated glomerular disease. Some immune complexes can enter the mesangium without crossing the glomerular basement membrane, as it does not completely surround all glomerular capillaries. Accumulation of immune complexes leads to mesangial infiltration of inflammatory cells and the production of local proinflammatory cytokines and autocoids. These substances enhance the immune complex–initiated inflammatory response, ultimately resulting in mesangial expansion, scarring, and obliteration of the glomerulus. The ultrastructure of the juxtaglomerular apparatus, which is part of the tubuloglomerular feedback mechanism, consists of the macula densa of the thick ascending limb and renin- and angiotensin II–producing granular cells of the afferent arteriole, as shown in Figure 33.5. Alport syndrome is a condition characterized by hematuria (blood in the urine) and progressive glomerulonephritis (inflammation of the glomerular capillaries). It accounts for 1% to 2% of all cases of end-stage renal disease (ESRD). Alport syndrome is caused by mutations in type IV collagen, a major component of the glomerular basement membrane. In 80% of patients, the disease is X-linked with mutations in the COL4A5 gene. Approximately 15% of patients have mutations in type IV collagen genes (COL4A3 and COL4A4) with autosomal recessive inheritance. The remaining 5% of patients have autosomal dominant disease resulting from heterozygous mutations in the COL4A3 or COL4A4 genes. In Alport syndrome, the glomerular basement membrane becomes irregular in thickness and fails to effectively filter blood cells and protein.
• Fig. 33.10 Anatomy of podocyte foot processes. This figure illustrates the proteins that make up the slit diaphragm between two adjacent foot processes. Nephrin and NEPH1 are membrane-spanning proteins that have large extracellular domains that interact. Podocin, also a membrane-spanning protein, organizes nephrin and NEPH1 in specific microdomains in the plasma membrane, which is important for signaling events that determine the structural integrity of podocyte foot processes. Many of the proteins that compose the slit diaphragm interact with adapter proteins inside the cell, including CD2-AP. The adapter proteins bind to the filamentous actin (F-actin) cytoskeleton, which in turn binds either directly or indirectly to proteins such as α3β1 and MAGI-1 that interact with proteins expressed by the glomerular basement membrane (GBM). α-act-4, α-actinin 4; α3β1, α3β1 integrin; α-DG, α-dystroglycan; CD2-AP, an adapter protein that links nephrin and podocin to intracellular proteins; FAT, a protocadherin that organizes actin polymerization; MAGI-1, a membrane-associated guanylate kinase protein; NHERF-2, Na+-H+ exchanger regulatory factor 2; P, paxillin; P-Cad, P-cadherin; Synpo, synaptopodin; T, talin; V, vinculin; Z, zona occludens. (Adapted from Mundel P, Shankland SJ. J Am Soc Nephrol 2002;13:3005.)
Mesangial cells are involved in development of immune complex–mediated glomerular disease. Because the glomerular basement membrane does not completely surround all glomerular capillaries (see
Fig. 33.9 ), some immune complexes can escape the blood and enter the mesangium without crossing the glomerular basement membrane. Accumulation of immune complexes induces mesangial infiltration of inflammatory cells and promotes local proinflammatory cytokine and autocoid production. These cytokines and autocoids enhance the immune complex– initiated inflammatory response, which can ultimately lead to mesangial expansion, scarring, and obliteration of the glomerulus.
Ultrastructure of the Juxtaglomerular Apparatus
The juxtaglomerular apparatus is one component of an important feedback mechanism, the tubuloglomerular feedback mechanism, described later in this chapter. Structures that make up the juxtaglomerular apparatus (see
Fig. 33.5 ) include: 1.
the macula densa of the thick ascending limb 2.
3.
reninand angiotensin II–producing granular cells of the afferent arteriole
Alport syndrome is characterized by hematuria (i.e., blood in the urine) and progressive glomerulonephritis (i.e., inflammation of the glomerular capillaries), and it accounts for 1% to 2% of all cases of ESRD. Alport syndrome is caused by mutations in type IV collagen, a major component of the glomerular basement membrane. In about 80% of patients with Alport syndrome the disease is X-linked with mutations in the COL4A5 gene. Some 15% of patients also have mutations in type IV collagen genes (COL4A3 and COL4A4); six have been identified, but the mode of inheritance is autosomal recessive. The remaining 5% of patients with Alport syndrome have autosomal dominant disease that arises from heterozygous mutations in the COL4A3 or COL4A4 genes. In Alport syndrome, the glomerular basement membrane becomes irregular in thickness and fails to serve as an effective filtration barrier to blood cells and protein.