URINARY SYSTEM

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14 URINARY SYSTEM

The urinary system has three critical functions: (1) to clear the blood of nitrogenous and other waste metabolic products by filtration and excretion; (2) to balance the concentration of body fluids and electrolytes, also by filtration and excretion; and (3) to recover by reabsorption small molecules (amino acids, glucose, and peptides), ions (Na+, C1−, Ca2+, PO3–), and water, in order to maintain blood homeostasis (Greek homoios, similar; stasis, standing).

The kidneys regulates blood pressure by producing the enzyme renin. Renin initiates the conversion of angiotensinogen (a plasma protein produced in liver) to the active component angiotensin II.

The kidneys is also an endocrine organ. It produces erythropoietin, a stimulant of red blood cell production in bone marrow (for the role of erythropoietin, see Chapter 6, Blood and Hematopoiesis). It also activates 1,25-hydroxycholecalciferol, a vitamin D derivative involved in the control of calcium metabolism (see vitamin D metabolism in Chapter 19, Endocrine System).

Kidneys

The urinary system consists of paired kidneyss and ureters and a single urinary bladder and urethra. Each kidneys has a cortex (subdivided into outer cortex and juxtamedullary cortex) and a medulla (subdivided into outer medulla and inner medulla).

The medulla is formed by conical masses, the medullary pyramids, with their bases located at the corticomedullary junction. A medullary pyramid, together with the associated covering cortical region, constitutes a renal lobe. The base of the renal lobe is the renal capsule. The lateral boundaries of each renal lobe are the renal columns (of Bertin), residual structures representing the fusion of primitive lobes within the metanephric blastema. The apex of each renal lobe terminates in a conic-shaped papilla surfaced by the area cribrosa (the opening site of the papillary ducts). The papilla is surrounded by a minor calyx. Each minor calyx collects the urine from a papilla dripping from the area cribrosa. Minor calyces converge to form the major calyces which, in turn, form the pelvis.

Organization of the renal vascular system

The main function of the kidneys is to filter the blood supplied by the renal arteries branching from the descending aorta.

The kidneyss receive about 20% of the cardiac output per minute and filter about 1.25 L of blood per minute. Essentially, all the blood of the body passes through the kidneyss every 5 minutes.

About 90% of the cardiac output goes to the renal cortex; 10% of the blood goes to the medulla. Approximately 125 mL of filtrate is produced per minute, but 124 mL of this amount is reabsorbed.

About 180 L of fluid ultrafiltrate is produced in 24 hours and transported through the uriniferous tubules. Of this amount, 178.5 L is recovered by the tubular cells and returned to the blood circulation, whereas only 1.5 L is excreted as urine.

We start our discussion by focusing on the vascularization of the kidneys (Figure 14-1).

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Figure 14-1 Vascularization of the kidneys

Oxygenated blood is supplied by the renal artery. The renal artery gives rise to several interlobar arteries, running across the medulla through the renal columns along the sides of the pyramids.

At the corticomedullary junction, interlobar arteries give off several branches at right angles, changing their vertical path to a horizontal direction to form the arcuate arteries, running along the corticomedullary boundary. The renal arterial architecture is terminal. There are no anastomoses between interlobular arteries. This is an important concept in renal pathology for understanding focal necrosis as a consequence of an arterial obstruction. For example, renal infarct can be caused by atherosclerotic plaques in the renal artery or embolization of atherosclerotic plaques in the aorta.

Vertical branches emerging from the arcuate arteries, the interlobular arteries, penetrate the cortex. As interlobular arteries ascend toward the outer cortex, they branch several times to form the afferent glomerular arterioles (see Figure 14-1).

The afferent glomerular arteriole, in turn, forms the glomerular capillary network, enveloped by the two-layered capsule of Bowman, and continues as the efferent glomerular arteriole. This particular arrangement, a capillary network flanked by two arterioles (instead of an arteriole and a venule) is called the glomerulus or arterial portal system. As discussed in Chapter 12, Cardiovascular System, the glomerular arterial portal system (Figure 14-2) is structurally and functionally distinct from the venous portal system of the liver.

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Figure 14-2 Arterial and venous portal systems

Both the glomerulus and the surrounding capsule of Bowman form the renal corpuscle (also called the malpighian corpuscle). The smooth muscle cell wall of the afferent glomerular arteriole contains epithelial-like cells, called juxtaglomerular cells, with secretory granules containing renin. A few juxtaglomerular cells may be found in the wall of the efferent glomerular arteriole.

Vasa recta

Depending on the location of the renal corpuscle, the efferent glomerular arteriole forms two different capillary networks:

1. A peritubular capillary network, surrounding the cortical segments of the superficial uriniferous tubules. The peritubular capillary network, lined by fenestrated endothelial cells, drains into the interlobular vein converging to the arcuate vein. Arcuate veins drain into the interlobar veins, which are continuous with the renal vein.
2. The vasa recta (straight vessels), formed by multiple branching of the efferent arterioles located close to the corticomedullary junction. The descending components of the vasa recta (arterial capillaries lined by continuous endothelial cells) extend into the medulla, parallel to the medullary segments of the uriniferous tubules, make a hairpin turn, and return to the corticomedullary junction as ascending venous capillaries lined by fenestrated endothelial cells.

Note that the vascular supply to the renal medulla is largely derived from the efferent glomerular arterioles. The descending vasa recta bundles penetrate to varying depths of the renal medulla, alongside the descending and ascending limbs of the loop of Henle and the collecting ducts. Side branches connect the returning ascending vasa recta to the interlobular and arcuate veins. Remember the close relationship of the vasa recta with each other and adjacent tubules and ducts. This is the structural basis of the countercurrent exchange and multiplier mechanism of urine formation as we will discuss later.

Difference between lobe and lobule

A renal medullary pyramid is a medullary structure limited by interlobar arteries at the sides. The corticomedullary junction is the base and the papilla is the apex of the pyramid.

A renal lobule is a cortical structure that can be defined in two different ways (see Figure 14-1): (1) The renal lobule is a portion of the cortex flanked by two adjacent ascending interlobular arteries. Each interlobular artery gives rise to a series of glomeruli, each consisting of an afferent glomerular arteriole, a capillary network, and the efferent glomerular arteriole. (2) The renal lobule consists of a single collecting duct (of Bellini) and the surrounding nephrons that drain into it. The straight portions of the nephrons, together with the single collecting duct, is called a medullary ray (of Ferrein). A medullary ray is the axis of the lobule (Figure 14-3).

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Figure 14-3 Medullary ray

Note that the cortex has many lobules and that each lobule has a single medullary ray.

The uriniferous tubule consists of a nephron and a collecting duct

Each kidneys has about 1.3 million uriniferous tubules surrounded by a stroma containing loose connective tissue, blood vessels, lymphatics, and nerves. Each uriniferous tubule consists of two embryologically distinct segments (Figure 14-4): (1) the nephron and (2) the collecting duct.

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Figure 14-4 Uriniferous tubule

The nephron consists of two components: (1) the renal corpuscle (300 μm in diameter) and (2) a long renal tubule (5 to 7 mm long).

The renal tubule consists of several regions: (1) the proximal convoluted tubule, (2) the loop of Henle, and (3) the distal convoluted tubule, which empties into the collecting tubule.

Collecting tubules have three distinct topographic distributions: a cortical collecting tubule (found in the renal cortex as the centerpiece of the medullary ray), an outer medullary collecting tubule (present in the outer medulla), and an inner medullary segment (located in the inner medulla).

Depending on the distribution of renal corpuscles, nephrons can be either cortical or juxtamedullary. Renal tubules derived from cortical nephrons have a short loop of Henle that penetrates just up to the outer medulla. Renal tubules from juxtamedullary nephrons have a long loop of Henle projecting into the inner medulla (Figure 14-5).

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Figure 14-5 Cortical and juxtamedullary nephrons

The renal corpuscle

The renal corpuscle, or malpighian corpuscle (Figure 14-6), consists of the capsule of Bowman investing a capillary tuft, the glomerulus.

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Figure 14-6 Renal corpuscle

The capsule of Bowman has two layers: (1) the visceral layer, attached to the capillary glomerulus, and (2) the parietal layer, associated with the connective tissue stroma.

The visceral layer is lined by epithelial cells called podocytes, reinforced by a basal lamina. The parietal layer is covered by a basal lamina supported by simple squamous epithelium and is continuous with the simple cuboidal epithelium of the proximal convoluted tubule.

A urinary space (Bowman’s space or capsular space), containing the plasma ultrafiltrate (primary urine), exists between the visceral and parietal layers of the capsule. The plasma ultrafiltrate contains trace amounts of protein. The urinary space is continuous with the lumen of the proximal convoluted tubule at the urinary pole, the gate through which the plasma ultrafiltrate flows into the proximal convoluted tubule. The opposite pole, the site of entry and exit of the afferent and efferent glomerular arterioles, is called the vascular pole.

The glomerulus consists of two components (Figure 14-7):

1. The glomerular capillaries, lined by fenestrated endothelial cells.
2. The mesangium, formed by mesangial cells embedded in the mesangial matrix.
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Figure 14-7 Components of the renal corpuscle visualized by light and electron microscopy

The renal corpuscle: Glomerular filtration barrier

The podocytes have long and branching cell processes that completely encircle the surface of the glomerular capillary. Both podocytes and fenestrated endothelial cells and their corresponding basal laminae constitute the glomerular filtration barrier.

The endings of the cell processes, the pedicels, from the same podocyte or adjacent podocytes, interdigitate to cover the basal lamina and are separated by gaps, the filtration slits. Filtration slits are bridged by a membranous material, the filtration slit diaphragm (Figure 14-8). Pedicels are attached to the basal lamina by α3β1 integrin.

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Figure 14-8 Glomerular filtration barrier

The podocyte filtration slit diaphragm consists of the protein nephrin interacting with nephrin molecules in a homophilic manner, and with the nephrin-related transmembrane proteins Neph1 and Neph2. Nephrin is anchored to actin filaments (within the pedicel) by the proteins podocin and CD2-associated proteins (CD2AP). The interaction of nephrin in the middle of the slit creates a filtering structure retarding the passage of molecules crossing the endothelial fenestrations and the basal laminae.

In addition to the components of the glomerular filtration barrier, other limiting factors controlling the passage of molecules in the plasma ultrafiltrate are size and electric charge. Molecules with a size less than 3.5 nm and positively charged or neutral are filtered more readily. Albumin (3.6 nm and anionic) filters poorly.

Clinical significance: Glomerular filtration defects

The fenestrated endothelial cells of the glomerular capillaries are covered by a basal lamina to which the foot processes of the podocytes attach (see Figure 14-8). Podocytes produce glomerular endothelial growth factor to stimulate the development of the endothelium and maintenance of its fenestrations.

The endothelium is permeable to water, urea, glucose, and small proteins. The surface of the endothelial cells is coated with negatively charged glycoproteins that block the passage of large anionic proteins.

The endothelial cell basal lamina, closely associated with the basal lamina produced by podocytes, contains type IV collagen, fibronectin, laminin, and heparan sulfate as major proteins.

Each type IV collagen monomer consists of three α chains forming a triple helix. There are six chains (α1 to α6) encoded by six genes (COL4A1 through COL4A6). Two domains of each monomer are important: (1) the noncollagenous (NC1) domain at the C-terminal and (2) the 7S domain at the N-terminal. The NC1 and 7S domains, separated by a long collagenous domain, are cross-linking domains required for formation of the type IV collagen network. A correctly assembled network is critical for maintaining the integrity of the glomerular basal lamina and its permeability function.

Type IV collagens are directly involved in the pathogenesis of three diseases. (1) Goodpasture syndrome, an autoimmune disorder consisting in progressive glomerulonephritis and pulmonary hemorrhage, caused by anti-α3(IV) antibodies binding to the glomerular and alveolar basal laminae. (2) Alport’s syndrome, a progressive inherited nephropathy, characterized by irregular thinning, thickening, and splitting of the glomerular basal lamina. Alport’s syndrome is transmitted by an X-linked recessive trait, is predominant in males, and involves mutations of the COL4A5 gene. Patients with Alport’s syndrome—often associated with hearing loss (defective function of the stria vascularis of the cochlea) and ocular symptoms (defect of the lens capsule)—have hematuria (blood in the urine) and progressive glomerulonephritis leading to renal failure. The abnormal glomerular filtration membrane enables the passage of red blood cells and proteins. (3) Benign familial hematuria, caused by a dominant inherited mutation of the COL4A4 gene, which does not lead to renal failure.

Clinical significance: Congenital nephrotic syndrome

Congenital nephrotic syndrome is caused by a mutation in the nephrin gene leading to the absence or malfunction of the podocyte slit filtration diaphragm. About 70 different mutations have been described. Affected children have massive proteinuria even in utero and the nephrotic syndrome develops soon after birth. Infants display abdominal distention, hypoalbuminemia, hyperlipidemia, and edema. Congenital nephrotic syndrome, particularly common in Finland, is lethal.

Mesangium

The mesangium, an intraglomerular structure interposed between the glomerular capillaries, consists of two components: (1) the mesangial cells and (2) the mesangial matrix. In addition, mesangial cells aggregate outside the glomerulus (extra-glomerular mesangial cells; see Figures 14-7 and 14-15) in a space limited by the macula densa and the afferent and efferent glomerular arterioles. Intraglomerular mesangial cells may be continuous with extraglomerular mesangial cells.

Mesangial cells are specialized pericytes with characteristics of smooth muscle cells and macrophages.

Mesangial cells are (1) contractile, (2) phagocytic, and (3) capable of proliferation. They synthesize both matrix and collagen, and secrete biologically active substances (prostaglandins and endothelins). Endothelins induce the constriction of afferent and efferent glomerular arterioles.

Mesangial cells participate indirectly in the glomerular filtration process by:

1. Providing mechanical support for the glomerular capillaries.
2. Controlling the turnover of the glomerular basal lamina material by their phagocytic activity.
3. Regulating blood flow by their contractile activity.
4. Secreting prostaglandins and endothelins.
5. Responding to angiotensin II.

The glomerular filtration membrane does not completely surround the capillaries (Figure 14-9). Immunoglobulins and complement molecules, unable to cross the filtration barrier, can enter the mesangial matrix. The accumulation of immunoglobulin complexes in the matrix induces the production of cytokines by mesangial cells that trigger an immune response leading to the eventual occlusion of the glomerulus.

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Figure 14-9 Functions and organization of the mesangium

Clinical significance: Immuno mediated glomerular diseases

The damage to the glomerulus can be initiated by immune mechanisms. Antibodies against glomerular components (cells and basal lamina) and antibody-complement complexes circulating in blood in patients with systemic autoimmune diseases can cause glomerular injury such as membranoproliferative glomerulonephritis (Figure 14-10), membranous glomerulonephritis and immunoglobulin A nephropathy (Berger’s disease).

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Figure 14-10 Pathology of the mesangium

Antibody-antigen complexes are not immunologically targeted to glomerular components. They are trapped in the glomerulus because of the filtration properties of the glomerular filtration barrier. A complicating factor is that trapped antibody-antigen complexes provide binding sites to complement proteins, which also contribute to the glomerular damage (see Chapter 10, Immune-Lymphatic System, for a review of the complement cascade).

As we have seen, autoantibodies can target domains of type IV collagen, a component of the glomerular filtration barrier. The binding of antibodies to specific domains of type IV collagen generates a diffuse linear pattern detected by immunofluorescence microscopy. In addition, the deposit of circulating antibody-antigen complexes produces a granular pattern. Systemic lupus erythematosus and bacterial (streptococci) and viral (hepatitis B virus) infections generate antibody-antigen complexes circulating in blood.

Immune complexes can deposit between the endothelial cells of the glomerular capillaries and the basal lamina (subendothelial deposits, see Figure 14-10), in the mesangium, and less frequently between the basal lamina and the foot processes of podocytes (subepithelial deposits).

Immune complexes produced after bacterial infection can cause the proliferation of glomerular cells (endothelial and mesangial cells) and attract neutrophils and monocytes. This condition, known as acute proliferative glomerulonephritis, is observed in children and is generally reversible with treatment. This disease is more severe in adults: it can evolve into rapidly progressive (crescentic) glomerulonephritis (Figure 14-11).

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Figure 14-11 Pathology of the renal corpuscle: Glomerulonephritis

A typical feature of crescentic glomerulonephritis is the presence of glomerular cell debris and fibrin, causing severe glomerular injury. The proliferation of parietal cells of the capsule of Bowman and migrating neutrophils and lymphocytes into the space of Bowman occur. Both the cellular crescents and deposits of fibrin compress the glomerular capillaries.

Juxtaglomerular apparatus

The juxtaglomerular apparatus is a small endocrine structure consisting of:

1. The macula densa (see Figure 14-7), a distinct region of the initial portion of the distal convoluted tubule.
2. The extraglomerular mesangial cells (see Figure 14-7).
3. The renin-producing cells (juxtaglomerular cells) of the afferent glomerular arteriole (see Figure 14-6) and, to a lesser extent, the efferent glomerular arteriole.

The macula densa is sensitive to changes in NaCl concentration and affects renin release by juxtaglomerular cells. Renin is secreted when the NaCl concentration or blood pressure falls. Extraglomerular mesangial cells (also called lacis cells) are connected to each other and to juxtaglomerular cells by gap junctions.

The juxtaglomerular apparatus is one of the components of the tubuloglomerular feedback mechanism involved in the autoregulation of renal blood flow and glomerular filtration.

The other component is the sympathetic nerve fibers (adrenergic) innervating the juxtaglomerular cells. Renin secretion is enhanced by norepinephrine and dopamine secreted by adrenergic nerve fibers. Norepinephrine binds to α1-adrenergic receptors in the afferent glomerular arteriole to cause vasoconstriction. There is no parasympathetic innervation.

We come back to the tubuloglomerular feedback mechanism when we discuss the renin-angiotensin-aldosterone regulatory mechanism (see Figure 14-18).

Proximal convoluted tubule: The reabsorption component

The plasma ultrafiltrate in the urinary space is transported by active and passive mechanisms to the proximal convoluted tubule (PCT), where about 70% of filtered water, glucose, Na+, Cl−, and K+, and other solutes are reabsorbed.

Cuboidal epithelial cells, held together by apical tight junctions, line the PCT and have structural characteristics suitable for reabsorption. They display the following features (Figure 14-12):

1. An apical domain with a well-developed brush border consisting of microvilli.
2. A basolateral domain with extensive plasma membrane infoldings and interdigitations.
3. Long mitochondria located between the plasma membrane folds provide adenosine triphosphate (ATP) for active transport of ions mediated by an Mg2+–dependent Na+, K+-activated pump.
4. Apical tubulovesicles and lysosomes provide a mechanism for endocytosis and breakdown of small proteins into amino acids. The movement of urea and glucose across the plasma membrane is mediated by a transport protein. Reabsorbed material enters the peritubular capillary network.
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Figure 14-12 Proximal convoluted tubule (PCT)

The driving force for water reabsorption is a transcellular osmotic gradient established by the reabsorption of solutes, such as NaCl and glucose. Because the PCT is highly permeable to water, water passes by osmosis across tight junctions (paracellular pathway) into the lateral intercellular space. An increase in the hydrostatic pressure in the intercellular compartment forces fluids and solutes to move into the capillary network.

The Fanconi syndrome is a renal hereditary (primary) or acquired (secondary) disease in which PCTs fail to reabsorb amino acids and glucose. Consequently, these substances are excreted in urine. The cause is a defective cellular energy metabolism resulting from a decrease in ATP levels attributed to the impaired activity of the Mg2+-dependent Na+ K+-activated ATPase pump. Cystinosis, caused by the accumulation of cystine in renal tubule cells, is the most common cause of Fanconi syndrome in children.

Loop of Henle

The loop of Henle reabsorbs about 15% of the filtered water and 25% of the filtered NaCl, K+, Ca2+, and HCO3−.

The loop of Henle consists of a descending limb and an ascending limb. Each limb is formed by a thick segment and a thin segment (Figure 14-13).

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Figure 14-13 Loop of Henle

The thick descending segment is a continuation of the PCT. The thick ascending segment is continuous with the distal convoluted tubule (DCT).

The length of the thin segments varies in cortical and juxtamedullary nephrons. Because the ascending limb is impermeable to water, filtered water reabsorption occurs exclusively in the descending limb, driven by an osmotic gradient between the tubular fluid and the interstitial fluid.

As in the PCT, an Na+, K+-ATPase pump in the ascending limb is a key element in the reabsorption of solutes. Inhibition of this pump by diuretics such as furosemide (Lasix) inhibits the reabsorption of NaCl and increases urinary excretion of both NaCl and water by reducing the osmolality of the interstitial fluid in the medulla.

The thick segments of the limbs are lined by a low cuboidal epithelium in transition with the epithelial lining of the proximal tubules. The thin segments are lined by a squamous simple epithelium.

Distal convoluted tubule

The DCT and the collecting duct reabsorb approximately 7% of the filtered NaCl. The distal portion of the DCT and the collecting ducts are permeable to water in the presence of antidiuretic hormone (ADH, or vasopressin).

NaCl enters the cell across the apical domain and leaves the cell by an Na+, K+-ATPase pump (Figure 14-14). The reabsorption of NaCl is reduced by thiazide diuretics that inhibit the apical domain transporting mechanism (see Figure 14-20).

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Figure 14-14 Distal convoluted tubule (DCT)

The active dilution of the tubular fluid initiated in the ascending segments of the loop of Henle continues in the DCT. Because the ascending segment of the loop of Henle is the major site where water and solutes are separated, the excretion of both dilute and concentrated urine requires the normal function of the loop of Henle.

The cuboidal epithelial cell lining of the DCT has the following characteristics (Figure 14-15; see also Figure 14-14):

1. Cuboidal cells are shorter than those in the PCT and lack a prominent brush border.
2. As in the PCT, the plasma membrane of the basolateral domain is infolded and lodges mitochondria.
3. In the macula densa, the cells display a reversed polarity: the nucleus occupies an apical position and the basal domain, containing a Golgi apparatus, faces the juxtaglomerular cells and extraglomerular mesangial cells. The macula densa, located at the junction of the ascending thick segment with the DCT, senses changes in Na+ concentration in the tubular fluid.

Collecting tubule (duct)

The collecting tubule (also called duct) is lined by a cuboidal epithelium composed of two cell types: principal cells and intercalated cells (Figure 14-16). Principal cells have an apical primary cilium and a basolateral domain with moderate infoldings and mitochondria. They reabsorb Na+ and water and secrete K+ in an Na+, K+-ATPase pump-dependent manner. Intercalated cells have apical microvilli and abundant mitochondria and secrete either H+ or HCO3−. Therefore, they are important regulators of acid-base balance. They also reabsorb K+.

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Figure 14-15 Juxtaglomerular cells and extramesangial cells

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Figure 14-16 Collecting tubule/duct

The primary cilium of principal cells is a mechanosensor of fluid flow and contents. The ciliary plasma membrane contains membrane-associated proteins polycystin-1 and polycystin-2. Polycystin-1 is regarded as a cell-cell and cell-extracellular matrix adhesive protein. Polycystin-2 acts as a Ca2+-permeable channel.

A mutation of either the gene PKD1, encoding polycystin-1, or PKD2, encoding polycystin-2, results in autosomal dominant polycystic kidneys disease (ADPKD). A complete loss of PKD1 or PKD2 gene expression results in the formation of massive renal cysts derived from dilated collecting ducts. Patients present with blood hypertension and progressive renal failure after their third decade of life. Renal dialysis and renal transplantation can extend the life spans of patients with ADPKD.

Interstitial cells

We noted in Figure 14-13 the presence of vertical stacks of interstitial cells extending from the loops of Henle to adjacent vasa recta like the rungs of a ladder. There are two populations of interstitial cells: renal cortical and medullary fibroblasts. Their function is the maintenance of renal architecture and production of erythropoietin. Synthetic erythropoietin is used in the treatment of anemia resulting from chronic renal failure or cancer chemotherapy. We discussed in Chapter 6, Blood and Hematopoiesis, the mechanism by which erythropoietin stimulates the production of red blood cells.

The cytoplasm of renal medullary fibroblast-like interstitial cells contains actin filaments. It has been suggested that interstitial cells secrete prostaglandins and may regulate papillary blood flow by contracting in response to hormonal stimulation. Lipid droplets can also be seen in their cytoplasm.

Activated interstitial fibroblasts and inflammatory cells (macrophages and lymphocytes) participate in interstitial nephritis (tubulointerstitial disease) caused by nephrotoxic drugs (such as heavy metals or hypersensitivity to penicillin) or by an immunologic mechanism (for example, lupus erythematosus).

EXCRETORY PASSAGES OF URINE

The urine released at the openings of the papillary ducts flows from the calyces and pelvis into the ureters and enters the urinary bladder. Peristaltic waves, spreading from the calyces along the ureter, force the urine toward the bladder.

The walls of the ureter and urinary bladder (Figure 14-17) contain folds (rugae). As the bladder fills with urine, the rugae flatten and the volume of the bladder increases with minimal increase in intravesical pressure. The renal calyces, pelvis, ureter, and urinary bladder are lined by a transitional epithelium, the urothelium, composed of basal and superficial cells. The epithelium and the subjacent lamina propria are surrounded by combined helical and longitudinal layers of smooth muscle fibers.

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Figure 14-17 Urinary bladder

In the bladder, a mixture of randomly arranged smooth muscle cells form the syncytial detrusor muscle. At the neck of the urinary bladder, the muscle fibers form a three-layer (inner longitudinal, middle circular, and outer longitudinal) internal functional sphincter.

Micturition, the process of emptying the urinary bladder, involves the micturition reflex, an automatic spinal cord reflex, and the stimulation of the detrusor muscle by parasympathetic fibers to contract.

Nephrolithiasis is a condition in which kidneys stones, composed of calcium salts, uric acid, or magnesium-ammonium acetate, form by crystallization when urine is concentrated. When the ureter is blocked by a stone, the contraction of the smooth muscle generates severe pain in the flank.

The male urethra is 20 cm long and consists of three segments. Upon leaving the urinary bladder, the prostatic urethra—lined by transitional epithelium—crosses the prostate gland, continues as a short membranous urethra segment, and ends as the penile urethra, which is enclosed by the corpus spongiosum of the penis (see Figure 21-12 in Chapter 21, Sperm Transport and Maturation). Both the membranous and penile urethra are lined by pseudostratified or stratified columnar epithelium.

The female urethra is 4 cm long and its longitudinally microfolded mucosa is covered by a stratified squamous epithelium that becomes moderately keratinized stratified squamous epithelium near the urethral meatus. The lamina propria contains elastic fibers and a venous plexus. An inner smooth muscle layer and an external striated muscle layer (continuous with the internal sphincter) are present in the wall. Additional structural details of the male and female urethra can be found in Chapter 21, Sperm Transport and Maturation, and Chapter 22, Follicle Development and the Menstrual Cycle, respectively.

REGULATION OF WATER AND NaCl ABSORPTION

Several hormones and factors regulate the absorption of water and NaCl (see Box 14-A for a review of terminology related to osmoregulation):

1. Angiotensin II stimulates NaCl and water reabsorption in the PCT. A decrease in the extracellular fluid volume activates the renin-angiotensin-aldosterone system and increases the concentration of plasma angiotensin II.
2. Aldosterone, synthesized by the glomerulosa cells of the adrenal cortex, stimulates the reabsorption of NaCl at the ascending limb of the loop of Henle, the DCT, and the collecting tubule. An increase in the plasma concentration of angiotensin II and K+ stimulates aldosterone secretion.
3. Atrial natriuretic factor (a 28-amino-acid peptide secreted by atrial cardiocytes; see Figure 12-3 in Chapter 12, Cardiovascular System) and urodilatin (a 32-amino-acid peptide analogue of atrial natriuretic factor) are encoded by the same gene and have similar amino acid sequences. Atrial natriuretic factor has two main functions: (1) it increases the urinary excretion of NaCl and water and (2) it inhibits the release of ADH from the neurohypophysis.

Box 14-A Review of terminology

• Osmolality is the concentration of solutes in body fluids. Alterations in osmolality depend on the gain or loss of water or on the loss or gain of osmoles (for example, glucose, urea, and salts). Plasma osmolality is kept normalized by the excretion of excess water, recovery of lost water, or by normalization of solute levels in the body.
• Molarity and molality refer to the concentration of a solute in a solution. The units of molarity are mol solute/L solution. The units of molality are mol solute/kg solvent. Osmolality and osmolarity represent the number of moles of solute particles in a solution (for example, Na+ and Cl− separately) instead of moles of compound in solution (for example, NaCl).
• Osmosis is the passive diffusion of water (the solvent) across a membrane from an area of low solute concentration to an area of high solute concentration. Osmotic equilibrium is reached when the amount of solute is equal on both sides of a membrane and the influx of water stops. Osmosis depends on the number of free dissolved particles without distinction between different molecular species (for example, Na+ and Cl−).
• Osmotic pressure is an indicator of how much water a compartment will draw into it through osmosis. Osmolarity and osmolality of the compartments on either side of a membrane determine the osmotic pressure of a compartment.
• Plasma membrane pumps and channels ensure that solutes are not distributed evenly on either side of a membrane as water does. If solutes distributed evenly, a concentration gradient would not exist to drive osmosis.
• Effective osmoles. A solute such as urea is not an effective osmole because it does not create osmotic pressure. Solutes such as Na+, K+, and Cl− are effective osmoles. Pumps and channels keep Na+ outside of cells and K+ inside of cells as effective osmoles.
• Aquaporins. The permeability of cells to water is facilitated by plasma membrane water channels called aquaporins. Different tissues have variable amounts of aquaporins and the cells may be more or less permeable to water than others. Antidiuretic hormone determines the insertion of aquaporins in the collecting duct, increasing its permeability to water.

Urodilatin is secreted by epithelial cells of the DCT and collecting tubule and inhibits NaCl and water reabsorption by the medullary portion of the collecting tubule. Urodilatin is a more potent natriuretic and diuretic hormone than atrial natriuretic factor.

4. Antidiuretic hormone, or vasopressin, is the most important hormone in the regulation of water balance. ADH is a small peptide (nine amino acids in length) synthesized by neuroendocrine cells located within the supraoptic and paraventricular nuclei of the hypothalamus.

When the extracellular fluid volume decreases (hypovolemia), ADH increases the permeability of the collecting tubule to water, thereby increasing water re-absorption. When ADH is not present, the collecting tubule is impermeable to water. ADH has little effect on the urinary excretion of NaCl.

Diabetes insipidus is a disorder associated with a low production of ADH (central diabetes insipidus) or a failure of the kidneys to respond to circulating ADH (nephrogenic diabetes insipidus). In the absence of ADH, water cannot be reabsorbed normally to correct hyperosmolality and hypernatremia (high levels of Na+ in plasma), polyuria (excessive volume of urine and frequency of urination), and polydipsia (thirst and increasing drinking) occur.

In diabetes mellitus, the concentration of glucose in plasma is abnormally elevated. Glucose overwhelms the reabsorptive capacity of the PCT, and intratubular glucose levels increase. Acting as an effective osmole, intratubular glucose hampers water reabsorption even in the presence of ADH. Osmotic diuresis is responsible for glucosuria (presence of glucose in urine), polyuria, and polydipsia in the diabetic patient. No glucosuria is observed in patients with diabetes insipidus.

RENIN-ANGIOTENSIN-ALDOSTERONE SYSTEM

This system is a significant component of the tubuloglomerular feedback system, essential for the maintenance of systemic arterial blood pressure when there is a reduction in the vascular volume. A reduction in vascular volume results in a decrease in the rate of glomerular filtration and the amount of filtered NaCl. A reduction in filtered NaCl is sensed by the macula densa, which triggers renin secretion and the production of angiotensin II, a potent vasoconstrictor.

The tubuloglomerular feedback system consists of:

1. A glomerular component: The juxtaglomerular cells predominate in the muscle cell wall of the afferent glomerular arteriole but are also present in smaller number in the efferent glomerular arteriole. Juxtaglomerular cells synthesize, store, and release renin. Activation of sympathetic nerve fibers results in the increased secretion of renin.
2. A tubular component: The macula densa mediates renin secretion after sensing the NaCl content in the incoming urine from the thick ascending segment of the limb of Henle. When the delivery of NaCl to the macula densa decreases, renin secretion is enhanced. Conversely, when NaCl increases, renin secretion decreases.

The renin-angiotensin-aldosterone system consists of the following components (Figure 14-18):

1. Angiotensinogen, a circulating protein in plasma produced by the liver.
2. The juxtaglomerular cells, the source of the proteolytic enzyme renin, which converts angiotensinogen to angiotensin I, a decapeptide with no known physiologic function.
3. The angiotensin-converting enzyme (ACE), a product of pulmonary and renal endothelial cells, which converts angiotensin I to the octapeptide angiotensin II.

Angiotensin has several important functions:

1. It stimulates the secretion of aldosterone by the adrenal cortex.
2. It causes vasoconstriction, which, in turn, increases blood pressure.
3. It enhances the reabsorption of NaCl by the PCTs of the nephron.
4. It stimulates ADH release.

Aldosterone acts primarily on principal cells of the collecting tubule and secondarily on the thick ascending limb of Henle to increase the entry of NaCl across the apical membrane. As with all steroid hormones, aldosterone enters the cell and binds to a cytosolic receptor. The aldosterone-receptor complex enters the nucleus and stimulates gene activity required for the reabsorption of NaCl.

COUNTERCURRENT MULTIPLIER AND EXCHANGER

The kidneyss regulate water balance and are the major site for the release of water from the body. Water is also lost by evaporation from the skin and the respiratory tract and from the gastrointestinal tract (fecal water and diarrhea).

Water excretion by the kidneys occurs independently of other substances, such as Na+, Cl−, K+, H+, and urea. The kidneys excrete either concentrated (hyper-osmotic) or diluted (hypo-osmotic) urine.

ADH regulates the volume and osmolality of the urine without modifying the excretion of other solutes. The primary action of ADH is to increase the permeability of the collecting tubule to water. An additional action is to increase the permeability of the collecting ducts at the medullary region to urea.

Figure 14-19 summarizes the essential steps of urine formation and excretion:

1. The fluid from the proximal convoluted tubules entering the loop of Henle is iso-osmotic with respect to plasma.
2. The descending limb of the loop of Henle is highly permeable to water and, to a lesser extent, to NaCl. As the fluid descends into the hyperosmotic interstitium, water and NaCl equilibrate and the tubular fluid becomes hyperosmotic.
3. When the fluid reaches the bend of the loop, its composition is hyperosmotic.
4. The ascending limb of the loop of Henle is impermeable to water. The concentration of NaCl in the lumen, greater than in the interstitium, is reabsorbed and enters the descending (arterial) portion of the vasa recta. Therefore, the fluid leaving this tubular segment is hypo-osmotic. This segment of the nephron is called the diluting segment.
5. The distal convoluted tubule and cortical portions of the collecting tubule reabsorb NaCl. In the absence of ADH, water permeability is low. In the presence of ADH, water diffuses out of the collecting tubule into the interstitium and enters the ascending (venous) segment of the vasa recta. The process of urine concentration starts.
6. The medullary regions of the collecting tubule reabsorb urea. A small amount of water is reabsorbed and the urine is concentrated.
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Figure 14-18 Renin-angiotensin-aldosterone system

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Figure 14-19 Countercurrent multiplier and exchanger

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Figure 14-20 Diuretics: Mechanism of action

The mechanism by which the loop of Henle generates the hypertonic interstitial gradient is known as countercurrent multiplication. This designation is based on the flow of fluid in opposite directions (countercurrent flow) within the two parallel limbs of the loop of Henle.

Note that:

1. The fluid flows into the medulla in the descending limb and out of the medulla in the ascending limb.
2. The countercurrent flow within the descending and ascending limbs of the loop of Henle “multiplies” the osmotic gradient between the tubular fluid in the descending and ascending limbs.
3. A hyperosmotic interstitium is generated by the reabsorption of NaCl in the ascending limb of the loop of Henle. This is an important step for the uriniferous tubule to excrete urine hyperosmotic with respect to plasma.
4. The concentration of NaCl increases progressively with increasing depth into the medulla. The highest concentration of NaCl is at the level of the papilla. This medullary gradient results from the accumulation of NaCl reabsorbed by the process of countercurrent multiplication.
5. The vasa recta transport nutrients and oxygen to the uriniferous tubules. They also remove excess water and solutes, continuously added by the counter-current multiplication process. An increase in blood flow through the vasa recta dissipates the medullary gradient.

Clinical significance: Mechanism of action of diuretics

The main function of diuretics is to increase the excretion of Na+ by inhibiting Na+ reabsorption by the nephron. The effect of diuretics depends on the volume of the extracellular fluid (ECF) compartment and the effective circulating volume (ECV). If the ECV decreases, the glomerular filtration rate (GFR) decreases, the load of filtered Na+ is reduced, and the reabsorption of Na+ by the PCT increases.

With these events in mind, you realize that the action of diuretics acting on the DCT can be compromised by the presence of lower concentrations of Na+ when the ECV is reduced.

Figure 14-20 provides a summary of the mechanism of action of osmotic diuretics, carbonic anhydrase inhibitors, loop diuretics, and thiazide diuretics.

Osmotic diuretics inhibit the reabsorption of water and solutes in the PCT and descending thin limb of the loop of Henle.

Carbonic anhydrase inhibitors inhibit Na+, HCO3−, and water reabsorption in the PCT.

Loop diuretics inhibit the reabsorption of NaCl in the thick ascending limb of the loop of Henle. About 25% of the filtered load of Na can be excreted by the action of loop diuretics.

Thiazide diuretics inhibit the reabsorption of NaCl in the DCT

Concept mapping

Urinary System

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Essential concepts

Urinary System

• Functions of the urinary system: (1) Filtration of the blood and excretion of waste metabolic products (from proteins, urea; from nucleic acids, uric acid; from muscle, creatinine; from hemoglobin metabolism, urobilin, which gives urine its color). (2) Regulation of water and electrolyte balance. (3) Regulation of arterial blood pressure (by maintaining blood volume and producing renin, a key initiator of the angiotensin-aldosterone cascade). (4) Regulation of erythropoiesis (through erythropoietin, produced by renal interstitial cells) and production of active vitamin D. Chronic renal diseases are associated with anemia because of a decrease in the production of erythropoietin.
• Each kidneys consists of a cortex and a medulla. The cortex is subdivided into outer cortex and juxtamedullary cortex. The medulla is subdivided into outer medulla and inner medulla. A renal lobe is a triangular-shaped structure consisting of a medullary pyramid—formed by the outer and inner medullary regions—covered by the corresponding cortex. The base of the triangle is lined by the capsule; the papilla is at the apex of the triangle; the lateral boundaries are the renal columns of Bertin. A minor calyx collects urine from each papilla covered by the area cribrosa, the opening site of the papillary ducts.

The organization of the renal vascular system is key for understanding renal structure and function. After entering the kidneys, the renal artery divides into interlobar arteries (running through the renal columns along the sides of the pyramids). At the corticomedullary junction, interlobar arteries change from a vertical to a horizontal direction to form the arcuate arteries. Vertical branches of the arcuate arteries enter the renal cortex and become interlobular arteries.

A renal lobule is defined as the portion of the cortex between two adjacent interlobular arteries. The axis of the lobule is occupied by a medullary ray (of Ferrein) consisting of a single collecting duct (of Bellini) collecting the fluid of the correponding intralobular nephrons. As you can see, renal lobules are cortical entities, whereas renal lobes are combined cortical-medullary structures. In fact, renal lobules are subcomponents of the renal lobes.

Interlobular arteries branch several times to form afferent arterioles. Each afferent arteriole forms the glomerular capillary network and continues as an efferent arteriole. This arteriolar-capillary-arteriolar arrangement (instead of arteriole-capillary-venule sequence) is called the glomerular or arterial portal system.

Blood vessels derived from the branching of the glomerular efferent arterioles form two different vascular networks: (1) a peritubular capillary network, surrounding the cortical segments of the uriniferous tubules, and (2) the vasa recta (straight vessels) with a descending arteriolar-capillary component and an ascending capillary-venous component, alongside the descending and ascending limbs of the loops of Henle, respectively. This vascular-tubular arrangement is essential for understanding the countercurrent multiplier and exchange mechanism of urine formation.

• The uriniferous tubule consists of two components of different embryologic origin: (1) the nephron and (2) the collecting tubule/duct.

The nephron consists of two components (1) the renal corpuscle and (2) the renal tubule. The renal corpuscle (of Malpighi) is formed by the capsule of Bowman investing the glomerular capillaries (the glomerulus). The renal tubule consists of the proximal convoluted tubule (PCT), the loop of Henle, and the distal convoluted tubule (DCT), which drains into the collecting tubule.

The collecting tubule can be found in the cortex (cortical collecting tubules), the outer medulla (outer medullary collecting tubule), and inner medulla (inner medullary collecting tubule). Depending on the distribution of renal corpuscles, nephrons can be either cortical nephrons or juxtamedullary nephrons.

The capsule of Bowman has two layers: a parietal layer (simple squamous epithelium supported by a basement membrane) and a visceral layer attached to the wall of the glomerular capillaries. The visceral layer consists of branched epithelial cells, the podocytes. The space between the parietal and visceral layers of the capsule of Bowman is the urinary space or Bowman’s space. The urinary space is continuous with the lumen of the PCT, the initial segment of the renal tubule. At this region, the urinary pole, the simple squamous epithelium of the parietal layer of the capsule of Bowman, becomes simple cuboidal with apical microvilli (brush border). This is the lining of the PCT.

The glomerulus consists of three components: (1) the glomerular capillaries, lined by fenestrated endothelial cells; (2) the mesangium, consisting of mesangial cells producing the mesangial matrix; and (3) the podocytes. Note that renal corpuscle and glomerulus designate different structures. A renal corpuscle includes the capsule of Bowman and the glomerulus. The designation glomerulus does not include the capsule of Bowman.

Mesangial cells are embedded in an extracellular matrix present between glomerular capillaries. Aggregates of mesangial cells can be seen outside the glomerulus (extraglomerular mesangial cells). Mesangial cells are pericyte-like cells with contractile and phagocytic properties. Mesangial cells participate indirectly in glomerular filtration by providing mechanical support to glomerular capillaries, turning over glomerular basal lamina components, and secreting vasoactive substances (prostaglandins and endothelins).

• An understanding of the structure of the glomerular filtration barrier is essential for grasping the clinical characteristics of proteinuria syndromes. The barrier has three layers: (1) the fenestrated endothelial cells of the glomerular capillaries; (2) the dual glomerular basal lamina (produced by endothelial cells and podocytes); and (3) the podocytes, including a filtration slit diaphragm between the interdigitating foot processes of podocytes.

The podocyte filtration slit diaphragm has a relevant role in glomerular filtration. Defects in some of its protein components lead to hereditary proteinuria syndromes. The filtration slit diaphragm is supported by intracellular F-actin present in pedicels, small podocyte cytoplasmic processes anchored to the dual basal lamina. The C-terminal intracellular segment of the protein nephrin is attached to F-actin by podocin, ZO-1, and CD2AP proteins. The N-terminal extracellular segment of nephrin interacts with another nephrin molecule (homophilic interaction) extending from an adjacent pedicel to form the backbone of the slit diaphragm.

The nephrin gene is mutated in congenital nephrotic syndrome of the Finnish type. Affected children display massive proteinuria and edema.

The dual glomerular basal lamina contains type IV collagen, a molecule directly involved in the pathogenesis of Good-pasture’s syndrome (an autoimmune disorder consisting in progressive glomerulonephritis and pulmonary hemorrhage caused by autoantibodies targeting the glomerular and alveolar basal lamina) and Alport’s syndrome (an inherited X-linked recessive nephropathy, predominant in males, and associated with hematuria, progressive glomerulonephritis, deafness, and ocular symptoms).

Glomerulonephritis defines an inflammatory process of the renal corpuscle. Antibody-antigen complexes circulating in blood trapped in the glomerular filtration barrier contribute to glomerular damage. Antibody-antigen complexes are produced by autoimmune diseases (systemic lupus erythematosus) or bacterial and viral infections (streptococci and hepatitis B virus). Acute proliferative glomerulonephritis observed in children is reversible. It is caused by proliferation of endothelial and mesangial cells in the presence of neutrophils. Rapid progressive (crescentic) glomerulonephritis consists in proliferation of parietal cells of the capsule of Bowman and infiltration of macrophages forming a crescent-like mass within the glomerulus. This form of glomerulonephritis is observed in Goodpasture syndrome.

• The juxtaglomerular apparatus consists of (1) the macula densa (an Na+ sensor present in the initial portion of the DCT); (2) the extraglomerular mesangial cells (a supporting cushion of the macula densa located at the vascular pole of the renal corpuscle); and (3) the renin-producing juxtaglomerular cells (modified smooth muscle cells of the wall of the afferent arteriole).

The juxtaglomerular apparatus is one of the components of the tubuloglomerular feedback mechanism participating in the autoregulation of renal blood flow and glomerular filtration.

• The PCT, a continuation of the urinary space (or Bowman’s capsular space), is the major reabsorption component of the nephron. The PCT is lined by a simple cuboidal epithelium with well-developed apical microvilli (brush border) and tubulovesicles and lysosomes involved in the endocytosis and breakdown of peptides into amino acids. A basolateral domain displays plasma membrane infoldings and interdigitations that lodge numerous mitochondria providing adenosine triphosphate (ATP) for active ion transport mediated by an Na+, K+–activated ATPase pump.

A paracellular transport pathway (across tight junctions) mobilizes, by osmosis, water into the lateral intercellular space. A transcellular transport pathway is involved in the reabsorption of solutes such as NaCl, peptides, and glucose.

Fanconi syndrome is a renal hereditary (primary) or acquired (secondary) disease in which amino acids and glucose are not reabsorbed and are found in urine. The cause appears to be a defect in the cellular energy metabolism decreasing the levels of ATP by the impaired activity of the Na+, K+ –activated ATPase pump. The accumulation of cystine in renal tubules (cystinosis leading to renal failure) is the most common cause of Fanconi syndrome in children.

• The loop of Henle consists of a descending limb and an ascending limb. Each limb is formed by a thick segment (lined by simple cuboidal epithelium) and a thin segment (lined by simple squamous epithelium). The descending thick segment is a continuation of the proximal convoluted tubule. The ascending thick segment is continuous with the distal convoluted tubule. The U-shaped thin segment forms most of the loop in juxtamedullary nephrons deep in the medulla. Recall that the loop of Henle of cortical nephrons penetrates up to the outer medulla.
• The DCT is lined by a simple cuboidal epithelium with a less developed apical brush border when compared with the lining epithelium of the PCT.

Tubulovesicles and lysosomes are less prominent. The basolateral domain is infolded and mitochondria are abundant at this location. A distinctive structure is the macula densa, a cluster of cells located at the junction of the ascending thick segment with the DCT. The macula densa faces the extraglomerular mesangial cells and is part of the juxtaglomerular apparatus.

It is important to remember for histologic identification purposes that both PCT and DCT are adjacent to the renal corpuscle. There are specific structural features to remember: although epithelial cells lining the PCT and DCT contain abundant basal mitochondria, epithelial cells of the DCT do not show the characteristic apical tubulovesicles and lysosomes observed in cells of the PCT. In addition, the brush border is more prominent in the PCT than in the DCT.

• The collecting tubules (also called ducts) originate in the cortical medullary rays. We have already seen that a medullary ray is the axis of a renal lobule, a cortical subdivision bordered laterally by adjacent interlobular arteries, branches of the arcuate artery. Cortical medullary rays join others to form wider papillary ducts in the papilla. Papillary ducts open on the surface of the papilla forming a perforated area cribrosa.

The lining epithelium is simple cuboidal and consists of two cell types: (1) principal cells, light cells with an apical nonmotile cilium and (2) intercalated cells, dark cells with apical microvilli and abundant mitochondria. A useful identification feature to recall is that the cell outline of the principal and intercalated cells is very distinct.

Principal cells respond to aldosterone, a mineralocorticoid produced by cells of the zona glomerulosa of the adrenal cortex.

The apical nonmotile cilium of principal cells is a mechanosensor receiving signals from the fluid contents in the tubular lumen. Ciliary bending by fluid flow or mechanical stimulation induce Ca2+ release from intracellular storage sites. The ciliary plasma membrane contains the polycystin-1/polycystin-2 protein complex. Polycystin-2 acts as a Ca2+-permeable channel.

Autosomal dominant polycystic kidneys disease (ADPKD) results from mutations in either two genes: PKD1, encoding polycystin-1, or PKD2, encoding polycystin-2. Extensive cystic enlargement of both kidneyss results from a complete loss of PKD1 or PKD2 gene expression. Blood hypertension preceding progressive renal failure is observed in patients with ADPKD. Renal dialysis and renal transplantation are the indicated treatments.

• Interstitial cells, mainly fibroblasts, can be found in the renal cortex and medulla. Their main functions are to maintain the renal architecture and produce erythropoietin, a major regulatory protein of erythropoiesis.

Activated interstitial fibroblasts and inflammatory cells (macrophages and lymphocytes) are involved in interstitial nephritis (also called tubulointerstitial disease) caused by nephrotoxic drugs or by an immunologic mechanism.

• The excretory passages of urine include the renal calyces and pelvis, ureters, and urinary bladder, lined by a transitional epithelium (urothelium) supported by a lamina propria and surrounded by spiral and longitudinally arranged layers of smooth muscle. The male urethra consists of three segments: prostatic urethra (lined by transitional epithelium), membranous urethra, and penile urethra (both lined by pseudostratified-to-stratified columnar epithelium. The penile urethra is surrounded by the corpus spongiosum. The female urethra is lined sequentially by transitional epithelium to stratified squamous epithelium to low keratinized stratified squamous epithelium. The wall of the female urethra consists of an inner smooth muscle layer surrounded by an external striated muscle layer.
• The renin-angiotensin-aldosterone system is essential for the maintenance of systemic blood pressure when there is a reduction in the blood volume or pressure. The system is triggered by a tubuloglomerular feedback mechanism originating in the juxtaglomerular apparatus. The tubular component is the Na+-sensing macula densa; the glomerular component is the renin-producing juxtaglomerular cells. The immediate objectives of the tubuloglomerular feedback mechanism are the regulation of the glomerular filtration rate (by controlling afferent and efferent arteriolar resistance; recall the glomerular arterial portal arrangement already discussed) and the release of renin from juxtaglomerular cells to produce angiotensin II.

The major steps leading to the production of angiotensin II and its activities are:

1. Renin converts angiotensinogen (produced in hepatocytes) to angiotensin I. Angotensin-converting enzyme (produced by pulmonary and renal endothelial cells) converts angiotensin I to angiotensin II.
2. Angiotensin II targets the hypothalamus to produce antidiuretic hormone (ADH, released by the neurohypophysis). Antidiuretic hormone stimulates water reabsorption in the collecting tubule. In diabetes insipidus, water cannot be normally reabsorbed in the collecting tubule because of a low production of antidiuretic hormone. In diabetes mellitus, the high concentration of intratubular glucose impairs water reabsorption and osmotic diuresis occurs. Both diabetes insipidus and mellitus are associated with hypernatremia, polydipsia, and polyuria. Glucose in urine (glucosuria) is not observed in patients with diabetes insipidus.
3. Angiotensin II targets the zona glomerulosa of the adrenal cortex to release aldosterone. Aldosterone reduces the excretion of NaCl at the level of the thick ascending segment of the loop of Henle, the DCT, and the collecting tubule.
4. Angiotensin II targets arterioles to produce vasoconstriction, which increases blood pressure.

• The loop of Henle creates an osmotic gradient causing water to flow out the collecting tubule into the surrounding interstitial tissue. A countercurrent multiplication in the loop of Henle maintains high solute concentration in the renal medulla. Countercurrent multiplication occurs because (1) the thin descending segment of the loop of Henle is permeable to water but has low permeability to salt; (2) the thin ascending segment is permeable to salt but not to water; and (3) the thick ascending segment reabsorbs salt by active transport and is impermeable to water. As you can see, countercurrent multiplication results in increasing salt concentration in the medullary interstitium with the descent of the loop of Henle segment. When ADH increases water permeability of the collecting duct, water can flow down its osmotic gradient into the salty medullary interstitium.

Water and some salt must find its way back from the salty interstitium to the bloodstream to reduce plasma osmolality. The parallel arrangement of the peritubular vasa recta with the U-shaped loop of Henle participates in the absorption of solute and water by countercurrent exchange: the arterial descending segment of the vasa recta absorbs some salt and the venous ascending segment of the vasa recta reabsorbs water. In this way, the loop of Henle–dependent countercurrent multiplication does not accumulate salt and water indefinitely in the interstitium with the help of the vasa recta–dependent countercurrent exchange.

• Diuretics are drugs that increase the output of urine (diuresis) by acting on specific membrane transport proteins. Inhibition of Na+ resorption by the nephron leads to an increase in the excretion of Na+ (natriuresis) and water.

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