Outline of the Main Excretory Systems

Typically, excretory organs function by integrating different functions, all based on transport processes. They:

Kidneys

Kidneys are organs whose function basically results from the multiplication of the functions of each elementary functional unit, the nephron. Human kidneys consist of (2-2.5) x 106 nephrons, and the masses of water and solutes that are turned over can be very high. As an example, in 2 h the human kidneys ultra-filtrate the entire volume of water present in the extracellular fluids and, at the same time, they reabsorb 99% of that volume leaving excess water, salts, catabo-lites, toxins, and secreted exogenous molecules (such as drugs) in the urine. Overall, the two kidneys of an adult human turn over 12 times the total extracellular fluid volume.

The function of nephrons is based on: (1) glomerular ultrafiltration ofwater and solutes from the blood; (2) tubular reabsorption of water and conserved molecules from the ultrafiltrate back into the blood; and (3) tubular secretion of ions and other waste products from blood to the tubulus.

The basic principles of ultrafiltration have been described above. Downstream the glomerulus (G), the tubulus of the nephron exhibits specialized regions: the proximal convoluted tubulus (PCT), the loop of Henle (LH , not in all nephrons), the distal convoluted tubulus (DCT), and the collecting duct (CD) (Figure 1c).

A massive reabsorption, accounting for ^80% of total ultrafiltrate volume, occurs iso-osmotically with respect to both the plasma and ultrafiltrate in PCT. Key components of this process are the Na+/K+ ATPase expressed in the membrane of the serosal side and the Na+-linked transporters in the membrane of the luminal side of brush border cells forming the wall of the tubulus. Cl_ follows the electrochemical gradient mainly by the paracellular pathway and by the intracellular pathway mediated by passive membrane Cl_ channels (Figure 3 a).

The brush border cells of PCT are also involved in the active excretion and active reabsorption of a number of organic solutes. To support such activities are: (1) the Na+/K+ ATPase expressed in the membrane at the ser-osal side, which provides the electrochemical Na

3Na+

Lumen

3Na+

Lactate r~

HCO3-Vascular side r~

Lactate

Hco3 Simporter

Organic anions

J°AT Endo

Lumen

Organic anions

J°AT Endo

Endogenous organic acid urate anionic drugs

Vascular side

Lumen

LoW PH,O

LoW PH,O

Lumen

Betaine Electrolytes For Birds

Blood flow (low P hydr)

Blood flow (low P hydr)

Urine concentration

Osmotic gradient

Urine concentration

Osmotic gradient

Figure 3 (a) Schematic representation of the transports responsible for the reabsorption of NaCl and NaHCO3 by the cells of PCT, the transport of the electrolytes generates an iso-osmotic reabsorption of water (not indicated). (b) Schematic representation of the transports responsible for the excretion of organic endogenous anions, anionic drugs, and hippuric acid mediated by the organic anion transporter (OAT), NaDC, Na-dicarboxylate transporter (specific for a-ketoglutarate); URAT, urate transporter. (c) Schematic representation of the transports at the level of cells in the ascending limb of the loop of Henle. These transports are responsible for the increase of osmotic pressure in the ultrafiltrate and peritubular medium of the loop of Henle (d). (d) Schematic representation of the osmotic gradients generated in the ultrafiltrate and peritubular liquid by the loop of Henle. The arrows within the tubulus indicate the flow of ultrafiltrate within the loop of Henle (descending limb and ascending limb); the arrows in the red circuit represent the blood flow within the peritubular vessels, the arrows inside the collecting duct (CD) indicate the flow of urine. The large arrows indicate the water flow based on osmotic forces that are responsible for the concentration of urine. The osmolarity increases in the direction of color darkening. In this representation, the DCT connecting the LH and CD (see right panel) is not shown.

h2o+co2

CO2+ h2o

gradient; (2) a number of organic anion transporters (OATs) for organic endogenous anions, anionic drugs, and hippuric acid; the Na-dicarboxylate transporter (NaDC, for a-chetoglutarate); and (3) the uric acid transporter (URAT). At the level of the membrane at the serosal side, the Na+-coupled transport of a-chetoglutarate by NaDC drives the short-circuit of this chetoacid that catalyzes the transport by OAT of organic anions. The organic anions are then transported to the lumen across the membrane at the luminal side. In this membrane lactate is also exchanged with urate by URAT. The scheme of such transports is given in Figure 3 b. It is worth noting that all transports of organic molecules are linked to the activity of Na+/K+ ATPase and to the passive Na+ fluxes that tend to dissipate the electrochemical potential of this ion.

The LH is the continuation of the proximal tubulus. Here, the tubulus is differently specialized in the so-called descending (DLH) and ascending (ALH) branches that are strongly different in their active transport and passive permeability properties. DLH is termed 'descending' because it follows a cortical-to-medullar direction within the kidney mass, ALH is termed 'ascending' because it is oriented in the opposite direction. DHL is made by epithelial cells without particular specialization for transport (not shown in Figure 3d). They are also characterized by very low passive permeability for sodium (Pd,Na), chloride (Pd,a) but high for water (Pd,w). The ALH part has a thick wall made by cells actively moving Na+ and Cl_, through a mechanism similar to that of the NaCl excretion by salt glands (see below), and characterized by very low Pdw (Figure 3 c). The overall function of LH is based on the following properties: (1) the transport activity of ALH makes the peritubular medium hyperosmotic; (2) the low Pdw of ALH does not interfere with the generation of this hyperosmoticity;

(3) the high Pdw of DLH together with its high PdNa and Pd,Cl allows for a rapid equilibration of the liquid present in DHL that also becomes hyperosmotic; and

(4) the countercurrent direction of tubular liquid flow also allows for the generation and maintenance of the characteristic functional signature of LH: an osmotic gradient in the peritubular liquid with a cortical-to-medullar direction, due to water and electrolytes short-circuit. This gradient does not modify the osmotic composition of urine at the end of LH but is of fundamental importance for water economy and for the so-called 'facultative water reabsorption' that involves the terminal part of the nephron, the collecting duct (CD). The LH is indeed present in the nephrons of animals that recover water from the ultrafiltrate and excrete a hyperosmotic urine due to the low availability of environmental water. In the distal convoluted tubulus (DCT), a further Na+ and Cl_ reabsorption occurs. The main role of this section of the nephron mainly resides in its responsiveness to endocrine regulation (via aldosterone that stimulates the reabsorption of electrolytes) and in the excretion of K+ (again via aldosterone that stimulates the potassium excretion) and of H+ (see below).

The final part of the nephron, the CD, is responsible for the selective reabsorption of water from the ultra-filtrate, transforming it into urine. In this function, the cells of CD participate as selective filters that have high permeability for water and very low permeability for electrolytes. Furthermore, the CD is juxtaposed to the LH and the ultrafiltrate flows concurrently with the osmotic gradient generated by LH. Water, therefore, moves from the ultrafiltrate to the peritubular liquid following an osmotic gradient and is constantly removed by the venous microcircuit. To ensure that low electrolyte and high water permeability specific, membrane-bound proteins named acquaporines are involved, whose expression depends on the activation of a hormone-sensitive protein, G-coupled receptor (Figure 3d).

How can such a system, so far described in terms of water and electrolyte permeability, function as an excretory system for nitrogen waste? Urea and the other nitrogen catabolites are ultrafiltrated at the glomerolus. Since the Pd coefficient of the tubular wall is very low, these solutes are not reabsorbed and become excreted in a concentrated urine: the amount of urea that is reabsorbed in the human kidney is of the order of 40% of the total ultrafiltrated urea.

The nephron is involved also in another excretory function: in combination with the respiratory epithelia it is involved in pH homeostasis and the removal of CO2 as metabolic waste. The cells forming the wall of PCT and of LH excrete H+ ions by the H+/Na+ antiporter. The movement of H+, then, depends on the electrochemical potential of Na+ ions and by the synthesis of carbonic acid catalyzed by the cytoplasmic carbonic anhydrase that provides an intracellular source of protons. The acidic dissociation of carbonic acid provides H+ to be exchanged with Na+ and HCO- that is symported with Na+ in the peritubular medium: overall, these cells excrete H+ ions (that are buffered by urinary NaHCO3 and Na2HPO4) and reabsorb NaHCO3 (Figure 3a). In the cells of DCT and CD, H+ ions are pumped by the H+-ATPase and HCO- ions are exchanged with Cl_ through an antiport system that is similar to that present in the plasma membrane of red blood cells (Figure 4). The source of H+ is the acidic dissociation of carbonic acid whose formation from metabolic CO2, diffusing into the tubulus cells, is catalyzed by carbonic anhydrase. Thus, acid is removed from blood via CO2 diffusion and H+ excretion through the H+-ATPase. Due to these transporting mechanisms, almost all parts of the nephron are capable of removing protons from the body fluids, thus participating in the pH homeostasis.

Figure 4 Regulation of pH through proton excretion. The cells of distal convoluted tubulus and of the collecting duct of the nephron are capable of H+ excretion in the urine through the H+-ATPase located in the luminal membrane. The source of H+ is the acidic dissociation of carbonic acid that is formed from metabolic CO2 by carbonic anhydrase that diffuses into the cells. Thus, acid is removed from blood via CO2 diffusion and active transport. The HCO3 /Cl- exchanger and the Na+/K+-ATPase located in the serosal side are also indicated.

Figure 4 Regulation of pH through proton excretion. The cells of distal convoluted tubulus and of the collecting duct of the nephron are capable of H+ excretion in the urine through the H+-ATPase located in the luminal membrane. The source of H+ is the acidic dissociation of carbonic acid that is formed from metabolic CO2 by carbonic anhydrase that diffuses into the cells. Thus, acid is removed from blood via CO2 diffusion and active transport. The HCO3 /Cl- exchanger and the Na+/K+-ATPase located in the serosal side are also indicated.

It is worth recalling that among fish, some species have dismissed glomeruli and evolved aglomerular nephrons that produce urine by tubular transport rather than by the ultrafiltration processes described above. The tubular activity involves transepithelial transport of organic solutes basically similar to those described above (Figure 3b) for mammalian PCT. In addition, transe-pithelial transport of sulfate, phosphate, chloride, sodium, and magnesium contributes to the driving force for generating the water flow. This, in turn, mediates excretion by increasing the luminal volume where waste solutes can be transported. Water reabsorption in the distal part of the nephron and urinary bladder concentrates unwanted solutes for excretion and minimizes water loss. Overall, the osmotic water secretion replaces glomerular ultrafiltration.

Malpighian Tubules

In malpighian tubules of insects, secretion from the cells forming the wall is the only mechanism for solute and water transport as ultrafiltration is not effective. Such cells are typically localized in the distal, blind-ended segment of the tubulus that secretes electrolytes, organic solutes, and water. The same mechanism occurs also for reabsorption of solutes and water in the proximal segments, located further downstream. Na+ and K+ are secreted into the lumen by active transport (Cl" by passive transport) generating an osmotic gradient that produces a water flux. The solute transport occurs via transcellular or paracellular movements. In the former case, the solute is transported from the peritubular medium (hemolymph) into the cell, through the basolateral membrane, moves in the cell interior, and is further transported into the lumen of the tubulus across the apical membrane. In the latter case, there is a direct

ATP ADP

Hemolymph

Figure 5 Schematic representation of transports across the membranes of cells forming the wall of malpighian tubulus. These cells actively transport electrolytes from the hemolymph to the lumen of tubulus via H+-ATPases, Na+,K+/H+ exchangers, K+ and Cl" channels, and Na+/K+/2CP (NKCC) exchangers. The scheme also shows the selective location of the various components in the polarized cell.

movement of solutes from the hemolymph to the lumen via the septate junctions located between adjacent cells. Such vectorial mass movements occur because the involved cells (principal cells) are functionally polarized, namely they express different pumps and carriers selectively as a function of the basolateral or apical side of the plasma membrane (Figure 5). In details, the secreting cells, 'principal cells', express the H+-ATPase localized in the apical membrane of their brush borders. By this active transport, an electrochemical gradient of H+ is formed across the brush border membrane. Thus, H+ ions tend to move dissipating such a gradient and are exchanged for Na+ and K+ through carriers selectively localized in the same apical brush-border membrane (by the same Na+-K+/H+ antiporter or by the combination of separated Na+/H+ and K+/H+ antiporters). As described in Figure 5, K+ ions enter the cells through both the Na+/K+/2Cl" simporter and the K+ conductance channels; excess cytoplasmic chloride is dissipated through Cl" conductance channels. Such channels are localized in the basolateral membrane. The Cl" ions move from the peritubular medium to the lumen, elec-trochemically driven by the sum of transepithelial Na+ and K+ transport and involve the paracellular pathway. The electrical coupling of active transcellular and passive paracellular transports dissipates the electrochemical gradient and maintains the electroneutrality between the two sides of the epithelium, in spite of the high rates of transepithelial electrolytes and water flows.

The water flux following the transport of electrolytes increases the hydrostatic pressure inside the tubulus lumen and provides the force that moves the liquid downstream to the proximal segment of the malpighian tubulus and then to the hindgut and the rectum. The intestinal

track is also involved in water reabsorption, so species that economize water produce a nitrogen waste, mostly uric acid, expelled in relatively dried feces. The function of malpighian tubuli changes during metamorphosis, as it occurs in the case of mosquitoes. In the larval stage they live in an aquatic environment but, on eclosion, they fly in the terrestrial habitat in the adult stage. In the former stage, solutes (but not water!) are reabsorbed from the lumen so that excess water is removed and the larvae remain in an osmotic steady state, in spite of their hyper-osmoticity with respect to the environmental water. As adults, mosquitoes switch from water excretion to water conservation excreting excess salts and metabolites with the minimum loss of water. Hematophagous or phytophagous insects can experiment a massive water and nutrient load during a meal, with uptake of water volumes that can exceed 12 times the insect body (like in the case of the blowfly Rodnius prolixus). In these cases, the increased urinary excretion allows for the elimination of excess water and salts.

Seawater

Figure 6 Schematic representation of electrolyte transport across the cells involved in salt gland of marine birds and reptiles, rectal gland of elasmobranchs, and teleosts gills (chloride cells CCs). The active excretion of NaCl from the body to the seawater depends on an electrochemical gradient to move Cr through the intracellular pathway and Na+ through paracellular pathway and the junctions between CC and the accessory cells (AC). The scheme also shows the selective location of the various components, Na+/K+-ATPases, K+ and Cr channels, and Na+/ K+/2CP (NKCC) exchangers, in the polarized cell.

Nephridia

Many aquatic and terrestrial invertebrates use the nephridia as excretory organs. They are tubular or branched structures in contact with the internal body fluids on one side and open to the environment on the other side. Protonephridia terminate as dead-end tubuli in the body cavity; specialized cells such as flame cells (ciliated) or solenocytes (flagellated) are the interfaces between the internal fluids and the lumen of the nephridia. Metanephridia collect the liquid from the celomatic cavity through a funnel-like structure called nephrostome. The coelomic fluid enters the tubulus, water and nutrients are reabsorbed, and the metabolic waste such as ammonia, urea, or uric acid is excreted. Although invertebrate nephridia and vertebrate kidneys evolved independently, there are remarkable analogies in the basic structure of solute transepithelial transport. Moreover, strong analogy exists also with the function mechanisms of extrarenal osmoregulatory structures such as shark rectal glands, avian salt gland, and gills (see below). The fundamental mechanism of excretion is based on the Cl_ conductance properties of a Cl_ secreting epithelium (Figure 6). While malpighian tubuli are connected to the midgut, nephridia are directly open to the body surface.

Extrarenal Osmoregulation

In this section we specifically address the osmoregulation mechanisms occurring in animals that possess kidneys for nitrogen waste excretion and also additional structures specifically related to osmoregulation. As mentioned above, excretion processes are strictly linked to osmore-gulation processes, although different structures can be involved.

Sodium chloride is the major electrolyte in extracellular body fluids of vertebrates. Many important functions depend on Na+/K+ ratio; therefore, losses of Na+ have to be replaced by its uptake from the environmental water or from food. Plants, herbivores, and all animals that live in hyposmotic environments have developed an efficient reabsorption of Na+. In marine vertebrates, the situation is completely different. Their preys are generally isotonic with seawater (Na+ - 450500 mM) and therefore they must excrete excess salt from their bodies by suitable transport mechanisms. While marine mammals use kidneys with elongated LH to produce hyperosmotic urine, all other vertebrates have developed extrarenal osmoregulator organs such as salt glands, rectal glands, and gills. These structures basically function according to the same transport mechanisms.

The typical cellular type has a brush border in the basolateral membrane (serosal side). In this membrane, the Na+/K+ ATPase, Na+/K+/2Cr co-transporter (NKCC), and potassium channels are present. The electroneutral uptake of chloride ions is due to the NKCC co-transporter that uses the sodium chemical gradient generated by Na+/K+ ATPase. Chloride leaves the cell across the luminal membrane via chloride channels. Potassium channels are responsible for recycling this ion across the basolateral membrane. Consequently, at the secretion of chloride in lumen, the electric potential increases between serosal and luminal membranes. This electrochemical gradient permits the diffusion of sodium into the lumen through the paracellular route, whereas water reaches the lumen by passive diffusion (Figure 6).

Salt glands are typical for many birds and four orders of reptiles - turtles, snakes, lizards, and crocodiles -adapted to marine life. In particular, marine birds have a highly developed salt-secreting gland situated on the head, above the orbit of the eye (supraorbital gland or glandula nasalis supraorbitalis). This gland is common to all birds but its size in species adapted to marine environment is 10-100 times larger than that of terrestrial birds. It has an excretory function with respect to the excess salts introduced with the diet.

Marine elasmobranches (Chondrichthyes) have higher plasma osmolarity (1000-1150 mOsm) than seawater, maintained by urea (—300mOsm), trimethylamine oxide (TMAO, — 100mOsm), and other osmolytes such as betaine. However, their body fluids have a smaller NaCl concentration (—560mOsm) and they also need to excrete out NaCl. The excretion of NaCl is carried out by the rectal gland, an osmoregulator organ that secretes a fluid with a high concentration of this salt (—500 mM), higher than in seawater and almost twice as high as in plasma. In the secretion fluid, there is no urea and TMAO. Rectal gland is thus able to regulate the volume of extracellular liquid into the body.

Marine teleosts maintain the ionic composition and osmolarity of their body fluids with gills. The branchial epithelium is composed of four different cellular types: mucous cells, pavement cells, nondifferentiated support cells, and chloride cells. Chloride cells are the site of the branchial NaCl secretion. These cells are characterized by well-developed mitochondria in close association with a greatly amplified membranous system. They present highly expressed Na+/K+ ATPase and NKCC in baso-lateral membrane, whereas the apical membrane is rich in

Cl_ channels. The secretory mechanism is the same of the salt glands described above (Figure 6). Sodium ions can diffuse in the environment through the tight junctions between adjacent chloride cells or between chloride cells and support cells. The tight junctions between pavement cells are deep and so form a high resistance barrier for sodium fluxes. Chloride cells are also involved in calcium ions absorption from environment. Ca2+ is transported into the body fluids by basolateral membrane calcium ATPases.

Excretion through the Gastrointestinal Tract

The gastrointestinal tract is an important compartment involved in the elimination of metabolites and xeno-biotics as it represents a barrier between the outside and inside of the body. Liver plays a key role for processing the materials absorbed by the gut, and the final destination of the xenobiotics, either food or drugs, depends on its activity. Bile is a secretion that assists intestinal digestion and absorption of lipids in vertebrates. It also represents an important route of elimination for environmental toxins, carcinogens, drugs, and xenobiotic metabolites as well as for endo-biotics such as cholesterol, bilirubin, and hormones. In particular, the biliar excretion is well suited for any potentially toxic molecule whose solubility is as low as to be not excreted through the urinary route: the presence in bile of biliary salts with detergent properties facilitates the excretion of poorly hydrophilic molecules. Bile is a fluid produced by hepatocytes by means of active transport of organic solutes. Water is moved by passive flux along an osmotic gradient; electrolytes and organic molecules also move by passive transport from the hepatocytes into the bile canaliculi

Bile canaliculus

Bile canaliculus

Bile Canaliculi

Figure 7 Schematic representation of transports responsible for bile formation in the canaliculi. Two hepatocytes (Hep.) and the canaliculus are represented. The hepatocytes express: the bile salt export pump (BSEP) capable of actively transporting bile salts (BS~); the canalicular conjugated export pump (a multidrug resistance-P-glycoprotein MRP, also capable of transfering anionic conjugates of bile salts OA-); the two multidrug resistance-associated proteins (MDRs) - the multidrug export pump, that actively transports cationic drugs (OC+), and the export pump for phospholipids (PC); the basolateral Na+/taurocholate co-transporting peptide (NTCP); and the organic anion transporting peptide (OATP).

Figure 7 Schematic representation of transports responsible for bile formation in the canaliculi. Two hepatocytes (Hep.) and the canaliculus are represented. The hepatocytes express: the bile salt export pump (BSEP) capable of actively transporting bile salts (BS~); the canalicular conjugated export pump (a multidrug resistance-P-glycoprotein MRP, also capable of transfering anionic conjugates of bile salts OA-); the two multidrug resistance-associated proteins (MDRs) - the multidrug export pump, that actively transports cationic drugs (OC+), and the export pump for phospholipids (PC); the basolateral Na+/taurocholate co-transporting peptide (NTCP); and the organic anion transporting peptide (OATP).

opened between adjacent cells as a microscopic mesh-work. Thus, hepatocytes also, similar to the other cell types involved in electrolytes and organic molecules transport so far described, are functionally polarized. The main organic molecules included in bile are bile salts (Na+ taurocholate and Na+ glycocholate, cholesterol derivatives conjugated with the aminoacids taurine or glycine), phospholipids, and cholesterol. ATP-driven transport systems are described as bile salt export pump (BSEP) and a conjugate export pump for divalent bile salts - a multidrug export pump for bulky amphipathic organic cations. The main membrane proteins responsible for the transport of bile components belong to the families of sodium-taurocholate co-transporting peptide (NTCP), organic anion transporting proteins (OATPs), multidrug resistance-associated protein (MDR), multidrug resistance-P-glycoprotein (MRP), and chloride-bicarbonate anion exchanger (AE). In Figure 7, an outline of the hepato-cytes transport system is summarized.

After secretion, the composition of the fluid is modified downstream of the canaliculi with reabsorption of water. Furthermore, reabsorption of bile components (mainly bile salts) occurs at the level of the intestine. The waste metabolites and xenobiotics are then eliminated with the feces.

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