The Glomerulus: The Parts That Form a Greater Whole

What is a glomerulus, and what does it do?

The glomerulus in its strictest form refers to the collection of specialized capillaries lined by a thin, fenestrated endothelium located at the initial portion of the nephron. These capillaries and endothelium, or glomeruli, are interconnected by mesangial cells and their matrix and lined by a basement membrane that is surrounded by visceral epithelial cells or podocytes. The cell bodies of the podocytes extend into a small cavity referred to as Bowman’s space or the urinary space. A layer of parietal epithelial cells and its basement membrane are just outside of the space and referred to as Bowman’s capsule (Figure 1). Anatomically, the collection of the glomeruli, mesangial cells and matrix, the two epithelial layers, the two basement membranes, and Bowman’s space are called the renal corpuscle. The terms renal corpuscle and glomerulus are often used interchangeably, although in strict anatomic terms, they are different (1).

Figure 1.

Schematic diagram of the renal corpuscle

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Mesangium, green; fenestrated endothelial cells, red; podocytes, blue; and parietal epithelial cells, purple.

The function of the renal corpuscle or the glomerulus is to filter the plasma to keep the cellular components and large proteins in the intravascular space while forming the ultrafiltrate containing water, electrolytes, and various other substances. This task is accomplished mainly by the structures located between the blood and Bowman’s space that are collectively referred to as the filtration barrier. The filtration barrier is made up of the endothelium, the glomerular basement membrane (GBM), and a slit diaphragm formed between the foot processes of the podocytes.

How do the glomerular endothelial cells select what goes into the ultrafiltrate?

The endothelial cells have a cell body with fenestrated cytoplasmic sheets encircling the capillary. The fenestrations allow ions and other substrates to pass through this layer and into the underlying basement membrane. The permeability of the endothelium is affected by vascular endothelial growth factor (VEGF). When VEGF is bound to the VEGF receptor of the glomerular endothelial cells, it induces the formation of fenestrations and increases the permeability of the endothelial cells (2).

How the endothelial cells selectively filter the plasma is controversial. The traditional theory (two pore or heteroporous model) suggests that the endothelial cells have many small pores and a few larger pores that allow for different-sized molecules to pass through to the GBM (3). The difficulty with this theory is that it cannot explain how albumin, with a diameter of approximately 70 Å, does not pass through the larger pores or clog the small pores. It has also been suggested that the luminal side endothelium is also negatively charged because of a glycocalyx (made of glycoproteins and glycosaminoglycans), which repels negatively charged substances like albumin (4). However, in recent years, an alternative explanation has been offered to account for how the filtration barrier prevents small proteins from entering or clogging the pores. This theory is referred to as the electrokinetic model (5). This model suggests that an electrical field is created by the convection and diffusion of differently charged ions across the filtration barrier. The electrical field prevents negatively charged proteins from crossing into the filtration barrier and will effectively move albumin away from the basement membrane by electrical current like an electrophoresis gel (5, 6).

What does the GBM do, and how can it lead to kidney disease?

The role the GBM plays in filtration is currently being debated. Although in vivo tracer studies suggest the GBM provides a charge- and size-selective barrier, in vitro models failed to show charge selectivity in isolated GBM, and size selectivity seems to be more the result of the cellular structures.

The GBM is made up of primarily type IV collagen, laminin, and sulfonated proteoglycans, with nidogen/entactin and types V and VI collagen also being present (1, 4). These materials are typically present in all other basement membranes in the body, but the GBM has unique type IV collagen α-chains (namely α3, α4, and α5) and laminin 11. These components unique to the GBM can lead to diseases such as Alport syndrome and Goodpasture disease if they are mutated or targeted by the immune system, respectively (1, 4).

What is the mesangium, and what does it do?

The endothelial cells line the entire 360° circumference of the capillary. Underneath the endothelial cell layer is the GBM. However, the GBM only forms an incomplete pouch-like covering. An analogy would be like laying a towel over a cardboard tube; the towel covers the tube but does not wrap all of the way around. The portion of the endothelium that is not covered by the GBM is actually covered by the mesangium. The mesangium is a collection of mesangial cells and their surrounding matrix that anchor the glomerular tuft. Each mesangial region can interact with a few different glomeruli for stability. The mesangial cells have cytoplasmic extensions with microfilaments that extend into the GBM to form the complete enclosure around the endothelium. By having the mesangium complete the enclosure around the endothelium, it allows the GBM to be pulled tight or relax as a compensatory mechanism for intracapillary hydraulic pressure (1). The mesangial cells also have receptors for vasopressin, angiotensin II, prostaglandin, TGF-β, and other vasoactive factors that can induce relaxation or contraction of the cell and thus apply tension to the GBM, leading to an alteration in glomerular filtration (7).

The mesangial cells make the mesangial matrix, a fibrillary substance composed of material similar to that of the GBM, which surrounds the cells and links to their cytoskeleton to provide stability and assistance during contraction. When exposed to stress, the mesangial cells also make various growth factors, including VEGF, NO, and other soluble factors, that can alter hemodynamic flow (8).

What is the role of the podocyte?

Outside of the GBM is the visceral epithelium (better known as podocytes). The podocytes are highly differentiated cells with cell bodies suspended above the basement membrane. Podocytes have cytoplasmic processes that subdivide numerous times to form finger-like projections called foot processes or pedicels, which encompass and attach to the lamina rara externa of the GBM. Each podocyte’s foot processes interdigitate with the neighboring cell, such that small filtration slits are formed. Between each slit are extracellular structures that interconnect each podocyte to its neighbor. These structures form what is termed the slit diaphragm (Figure 2).

Figure 2.

Transmission electron microscopy image of a podocyte

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(1) Fenestrated endothelial cell; (2) glomerular basement membrane; (3) podocyte foot process. Arrows indicate the slit diaphragm.

Reprinted with permission from Patricia M. Zerfas (Division of Veterinary Resources, Office of Research Services, National Institutes of Health).

Podocytes are crucial to filtration, and it is well established that a fully functional slit diaphragm is necessary for preventing proteinuria. One means by which podocytes regulate filtration is by producing VEGF, which will then regulate the permeability of the glomerular endothelium. Podocytes have also been shown to actively endocytose proteins and other components from the ultrafiltrate (4).

In healthy animals, podocytes generally appear stationary, but when under stress or in vitro, podocytes become very dynamic and will cluster together or migrate in response to the stress (9). Movement is accomplished by the many and complex networks of microtubules, microfilaments, and actin filaments that are present throughout the cell but particularly concentrated in the foot processes. To move in response to stress may be adaptive, because podocytes lack the ability to replicate in vivo (4).

Why are parietal epithelial cells important?

At the vascular pole, where the afferent arteriole enters and divides into the capillaries and the efferent arteriole exits, the podocytes and parietal epithelial cells are in contact with each other. The parietal epithelium, however, looks more like squamous cells with the broad cytoplasm, few organelles, and lack of foot processes. The parietal cells line the basement membrane of Bowman’s capsule, function as a final barrier for filtration, and funnel the ultrafiltrate into the proximal tubule. In animal models, when the parietal layer is compromised, molecules will spill out into the periglomerular space. Another important feature of the parietal epithelium is that parietal cells can differentiate into podocytes and repopulate the glomerular tuft after podocyte loss (10). The repopulation of the glomerular tuft by parietal epithelial cells may be the reason behind the adhesions formed between the glomerular tuft and Bowman’s capsule during focal segmental glomerular sclerosis (FSGS) or the formation of glomerular crescents in rapidly progressive glomerulonephritis (1).

References

1. Fenton RA, Praetorius J Anatomy of the kidney. In: Brenner and Rector’s The Kidney, edited by Skorecki K, Taal MW, Philadelphia, Elsevier, 2016, pp. 42–82.

2. Roberts WG, Palade GE Increased microvascular permeability and endothelial fenestration induced by vascular endothelial growth factor. J Cell Sci 1995; 108:2369–2379.

3. Oberg CM, Rippe B A distributed two-pore model: Theoretical implications and practical application to the glomerular sieving of Ficoll. Am J Physiol Renal Physiol 2014; 306:F844–F854.

4. Kriz W, Elger M Renal anatomy. In: Comprehensive Clinical Nephrology, 5th ed., edited by Johnson RJ, Feehally J, Floege J, Philadelphia, Elsevier, 2015, pp. 2–13.

5. Moeller MJ, Kuppe C Point: Proposing the electrokinetic model. Perit Dial Int 2015; 35:5–8.

6. Hausmann R, et al. Electrical forces determine glomerular permeability. J Am Soc Nephrol 2010; 21:2053–2058.

7. Schlondorff D The glomerular mesangial cell: An expanding role for a specialized pericyte. FASEB J 1987; 1:272–281.

8. Schlondorff D, Banas B The mesangial cell revisited: No cell is an island. J Am Soc Nephrol 2009; 20:1179–1187.

9. Hackl MJ, et al. Tracking the fate of glomerular epithelial cells in vivo using serial multiphoton imaging in new mouse models with fluorescent lineage tags. Nat Med 2013; 19:1661–1666.

10. Eng DG, et al. Glomerular parietal epithelial cells contribute to adult podocyte regeneration in experimental focal segmental glomerulosclerosis. Kidney Int 2015; 88:999–1012.