Figure 1913

Immunofluorescent-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 exclusively 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. x360. (Courtesy of Dr. Kevin J. McCarthy.)

Mesangium

The renal corpuscle contains an additional group of cells called mesangial cells. These cells and their extracellular matrix constitute the mesangium. It is most obvious at the vascular stalk of the glomerulus and at the interstices of adjoining glomerular capillaries. Mesangial cells are positioned much the same as pericytes, in that they are enclosed by the basal lamina of the glomerular capillaries (see Fig. 19.10). The mesangial cells are not entirely confined to the renal corpuscle; some are located outside the corpuscle along the vascular pole, where they are also designated as lacis cells and form part of what is called the juxtaglomerular apparatus (see Fig. 19.7).

Although all of the functions of mesangial cells are not yet fully understood, the following functions have been demonstrated:

• Phagocytosis. Mesangial cells remove trapped residues and aggregated proteins from the GBM, thus keeping the glomerular filter free of debris.

• Structural support. Mesangial cells provide support for the podocytes in the areas where the epithelial basement membrane is absent or incomplete.

• Secretion. Mesangial cells synthesize and secrete a variety of molecules such as interleukin-1 (IL-1) and platelet-derived growth factor (PDGF), which play a central role in response to glomerular injury.

The primary function of the mesangial cells is believed to be to clean the GBM. 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 basement membrane. Mesangial cells are contractile. Thus, they may also play a role in regulating glomerular blood flow.

Embryologically, mesangial and juxtaglomerular cells (discussed below) 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.

Juxtaglomerular Apparatus

The juxtaglomerular apparatus includes the macula densa, the juxtaglomerular cells, and the extraglomerular mesangial cells

Lying directly adjacent to the afferent and efferent arterioles and adjacent to some extraglomerular mesangial cells at the vascular pole of the renal corpuscle is the terminal portion of the distal straight tubule of the nephron. At this site the wall of the tubule contains cells that are referred to collectively as the macula densa. When viewed in the light microscope, the cells of the macula densa are distinctive, in that they are narrower and usually taller than other distal tubule cells. The nuclei of these cells appear crowded, even to the extent that they appear partially superimposed over one another, thus the name "macula densa."

In this same region, the smooth muscle cells of the adjacent afferent arteriole (and, sometimes, the efferent arteriole) are modified. They contain secretory granules, and their nuclei are spherical, as opposed to the typical elongate smooth muscle cell nucleus. These juxtaglomerular cells (see Fig. 19.7) require special stains to reveal the secretory vesicles in the light microscope.

For years, cardiologists and nephrologists believed that chronic essential hypertension, the most common form of hypertension, was somehow related to an abnormality in the renin-angiotensin-aldosterone system. However, 24-hour urine renin levels in such patients were usually normal. Not until a factor in the venom of a South American snake was shown to be a potent inhibitor of ACE in the lung did investigators have both a clue to the cause of chronic essential hypertension and a new series of drugs with which to treat this common disease.

The "lesion" in chronic essential hypertension is now believed to be excessive production of angiotensin II in the lung. Development of the so-called ACE /n/i/ft/fors-captopril, enalapril, and related derivatives of the original snake venom factor-has revolutionized the treatment of chronic essential hypertension. These antihypertensive drugs do not cause the often-dangerous side effects of the diuretics and ^-blockers that were previously the most commonly used drugs for control of this condition.

The juxtaglomerular apparatus regulates blood pressure by activating the renin-angiotensin-aldosterone system

In certain physiologic (low sodium intake) or pathologic conditions (decrease in volume of circulating blood due to hemorrhage or reduction in renal perfusion due to compression of the renal arteries) juxtaglomerular cells are responsible for activating the renin-angiotensin-aldosterone system. This system plays an important role in maintaining sodium homeostasis and renal hemodynamics. The granules of the juxtaglomerular cells contain an aspartyl protease, called renin, which is synthesized, stored, and released into the bloodstream from the modified smooth muscle cells. In the blood, renin catalyzes the hydrolysis of circulating a2-globulin, angiotensinogen, to produce the decapeptide angiotensin I. Then

• Angiotensin I is converted to the active octapeptide angiotensin II by angiotensin-converting enzyme (ACE) present on the endothelial cells of lung capillaries.

• Angiotensin II stimulates the synthesis and release of the hormone aldosterone from the zona glomerulosa of the adrenal gland (see page 665).

• Aldosterone, in turn, acts on collecting ducts to increase reabsorption of sodium and concomitant reabsorption of water, thereby raising blood volume and pressure.

• Angiotensin II is also a potent vasoconstrictor that has a regulatory role in the control of renal and systemic vascular resistance.

The juxtaglomerular apparatus functions both as an endocrine organ that helps to regulate blood composition and volume and as a sensor of blood composition and vol ume. Decreased blood volume or decreased sodium concentration in the blood are believed to be stimuli for the release of renin by the juxtaglomerular cells. The cells of the macula densa monitor NaCl concentration in the afferent arteriole and regulate the release of renin by the juxtaglomerular cells in a paracrine manner. An increase in blood volume sufficient to cause stretching of the juxtaglomerular cells in the afferent arteriole may be the stimulus that closes the feedback loop and stops secretion of renin.

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