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Glomerulus


Glomerulus
The glomerulus (or renal corpuscle) consists of the glomerular capillaries and the epithelium-lined sac that surrounds and invests them, known as Bowman’s capsule.

The glomerular capillaries originate from the afferent arteriole and drain into an efferent arteriole. They are arranged in a tuft about 200 m in diameter, which is anchored to a central stalk of mesangial cells and matrix. The walls of the glomerular capillaries contain three layers. The innermost layer consists of endothelial cells. The second layer consists of glomerular basement membrane (GBM). The outermost layer consists of podocytes, also known as visceral epithelial cells.
Bowman’s capsule, the first part of the nephron, consists of the two layers of epithelial cells that invest the glomerular capillaries. The podocytes (visceral epithelial cells) in the capillary wall constitute the inner layer of Bowman’s capsule. The parietal epithelial cells, which are continuous with the podocytes at the base of the capillary tuft, constitute its outer layer. The area between the podocyte and parietal epithelial cell layers is known as Bowman’s space.

STRUCTURE AND HISTOLOGY OF THE GLOMERULUS

The Capillary Wall
As blood passes through the glomerular capillaries, plasma and small, non-protein bound solutes are freely filtered across the three layers of the capillary wall into Bowman’s space, which leads to the proximal tubule. These three capillary wall layers, however, act as a critical barrier to the filtration of cells and larger plasma molecules, such as proteins, based on their size and charge.
The endothelial cells, which line the inner surface of the capillaries, are inconspicuous and possess a thin, attenuated cytoplasm. Their nuclei are generally located near the mesangial stalk, so as not to interfere with filtration. These cells contain fenestrations that are approximately 70 to 100 nm in diameter, which may serve as an initial size-based filtration barrier. The cell surfaces are also coated with a negatively charged glycocalyx that projects into the fenestrations and provides a charge-based filtration barrier.
The GBM lines the outer surface of the endothelial cells and is continuous with the basement membrane of Bowman’s capsule. It is synthesized by both endothelial cells and podocytes, and it consists of three layers: a thin lamina rara interna, a thick central lamina densa, and a thin lamina rara externa. Together, these layers measure approximately 300 to 350 nm across, being somewhat thicker in males than in females. The GBM consists primarily of type IV collagen and other proteins, such as laminin and nidogen (also known as entactin). The tight arrangement of these proteins contributes to the size-based filtration barrier. In addition, the GBM contains negatively charged proteoglycans that contribute to the charge-based filtration barrier. The potential space between the endothelial cells and GBM is known as the subendothelial space, while the potential space between the GBM and the podocytes is known as the subepithelial space.
The podocytes are large cells with prominent nuclei and other intracellular organelles. Their cytoplasm is elaborately drawn out into long processes that give rise to fingerlike projections known as foot processes (pedicels). These foot processes attach to the outer surface of the GBM and interdigitate with those from adjacent podocytes. They also lie between the podocyte cell bodies and the GBM, forming a subpodocyte space. The space between adjacent foot processes is generally about 25 to 60 nm. A structure known as the slit diaphragm spans this distance. It consists of an 11 nm-wide central filament attached to adjacent podocyte cell membranes by cross-bridging proteins arranged in a zipper-like configuration. The pores formed between the central filament, cell membranes, and cross-bridges have been measured as approximately 4  14 nm. These small pores in the slit diaphragm make a critical contribution to the size-based filtration barrier. In addition, the podocytes are lined by a negatively-charged glycocalyx, which likely contributes to the charge-based barrier.
The relative contributions of the three layers of the capillary wall to the filtration barrier remain controversial. The slit diaphragm is likely the main obstacle to protein diffusion. Indeed, glomerular diseases that cause loss of protein into the urine (proteinuria) generally cause a process known as foot process effacement, in which foot processes retract and shorten, disrupting slit diaphragms and opening a wide space for the passage of proteins. Nonetheless, disruption of the endothelial layer or GBM has also been shown to cause proteinuria, suggesting that these layers also make important contributions.

FINE STRUCTURE OF THE GLOMERULUS

Additional Cell Types
The mesangial cells provide structural support to the glomerular capillaries. These cells are irregularly shaped and send long cytoplasmic processes between endothelial cells. They are similar to modified smooth muscle cells and stain positive for smooth muscle actin and myosin. These cells can contract in response to various signals, narrowing the capillary loops and reducing glomerular flow. Signals that modulate mesangial tone include angiotensin II (see Plate 3-18), antidiuretic hormone (see Plate 3-17), norepinephrine, and thromboxane. In addition, mesangial cells are capable of phagocytosing local macromolecules and immune complexes, as well as generating inflammatory mediators in response. The mesangial cells are embedded in the mesangial matrix, which contains collagen, various proteoglycans, and other molecules. In histologic sections of normal glomeruli, one or two mesangial cells are typically seen per matrix area, with a greater number seen in certain pathologic states.
The parietal epithelial cells are flat squamous cells with sparse organelles. They are continuous with the visceral epithelial cells near the base of the glomerular capillary tuft and with the cells of the proximal tubule at the opposite side of the glomerulus. In histologic sections of normal glomeruli, one or two layers of parietal epithelial cells may be seen. In severe, rapidly progressive glomerular disease, additional layers of parietal cells may be seen.

ELECTRON MICROSCOPY OF THE GLOMERULUS

The Juxtaglomerular Apparatus
The juxtaglomerular apparatus is a specialized structure that consists of components from both the glomerulus and the distal tubule of its associated nephron.
The glomerular components include the terminal afferent arteriole, initial efferent arteriole, and extraglo-merular mesangium (also known as the lacis or as the cells of Goormaghtigh). The nephron supplied by this glomerulus loops around so that its thick ascending limb contacts the extraglomerular mesangium. The region of the thick ascending limb that makes direct contact with the extraglomerular mesangium contains specialized cells and is known as the macula densa.
Because of this arrangement, the distal tubule is able to provide feedback to the glomerulus to modulate the filtration rate. In the setting of inadequate tubular flow, for example, the macula densa triggers dilation of the afferent arteriole, which increases the filtration rate, and stimulates renin secretion from specialized cells, known as granular cells, in the walls of the afferent and efferent arterioles. (For details, see Plate 3-18.)
The extraglomerular mesangial cells are continuous with and resemble normal mesangial cells. They are linked to the granular cells via gap junctions, and they share a basement membrane and interstitium with the adjacent macula densa cells. Thus the extraglomerular mesangium appears to serve as the signaling intermediary between the tubular and vascular components of the juxtaglomerular apparatus.
The granular cells are similar to ordinary smooth muscle cells but have sparser smooth muscle myosin and contain numerous renin-filled vesicles. Because they produce large quantities of hormones, these cells also feature a prominent endoplasmic reticulum and Golgi apparatus.
Finally, the macula densa cells appear distinct from the neighboring tubular cells; a detailed description is available on Plate 1-25.