Tubular transport proximal tubule

Excretion via the kidney can be a straightforward question of glomerular filtration, followed by passage down the kidney tubules into the bladder. However, there can also be excretion and reabsorption across the tubular wall. This may happen if an ionized form within the tubule is converted into its nonpolar nonionized form because of a change in pH. The nonionized form can then diffuse across the tubular wall into plasma. Additionally, there are active transport systems for the excretion of lipophilic acids and bases across the wall of the proximal tubule. The antibiotic penicillin can be excreted in this way. 

More simply, in the early regions of the tubule (proximal tubule and Loop of Henle), Na+ ions leave the lumen and enter the tubular epithelial cells by way of passive facilitated transport mechanisms. The diffusion of Na+ ions is coupled with organic molecules or with other ions that electrically balance the flux of these positively charged ions. In the latter regions of the tubule (distal tubule and collecting duct), Na+ ions diffuse into the epithelial cells through Na+ channels. 

An essential requirement for diffusion of Na+ ions is the creation of a concentration gradient for sodium between the filtrate and intracellular fluid of the epithelial cells. This is accomplished by the active transport ofNa+ ions through the basolateral membrane of the epithelial cells (see Figure 19.4). Sodium is moved across this basolateral membrane and into the interstitial fluid surrounding the tubule by the Na+, K+-ATPase pump. As a result, the concentration of Na+ ions within the epithelial cells is reduced, facilitating the diffusion of Na+ ions into the cells across the luminal membrane. Potassium ions transported into the epithelial cells as a result of this pump diffuse back into the interstitial fluid (proximal tubule and Loop of Henle) or into the tubular lumen for excretion in the urine (distal tubule and collecting duct). 

Carbonic anhydrase inhibitors such as acetazolamide act in the proximal tubule. These drugs prevent the formation of H+ ions, which are transported out of the tubular epithelial cell in exchange for Na+ ions. These agents have limited clinical usefulness because they result in development of metabolic acidosis. 

Apart from glomerular filtration (B), drugs present in blood may pass into urine by active secretion. Certain cations and anions are secreted by the epithelium of the proximal tubules into the tubular fluid via special, energyconsuming transport systems. These transport systems have a limited capacity. When several substrates are present simultaneously, competition for the carrier may occur (see p. 268). 

The kidneys are susceptible to toxicity from xenobiotics (Fig. 7.1) because they too have a high blood flow. Cells of the tubular nephron face double-sided exposure, to agents in the blood on the basolateral side and in the Altered urine on the luminal side. Proximal tubule cells are generally the site of nephrotoxicity, since these cells have an abundance of cytochrome P450 and can transport organic anions and cations from the blood into the cells, thereby concentrating these chemicals manyfold. 

An important functional characteristic of the proximal tubule is that fluid reabsorption is isosmotic that is, proximal reabsorbed tubular fluid has the same osmotic concentration as plasma. Solute and water are transported in the same proportions as in the plasma because of the high water permeability of the proximal tubule. Thus, the total solute concentration of the fluid in the proximal convoluted tubule does not change as the fluid moves toward the descending loop of Henle. The corollary of this high water permeability is that unabsorbable or poorly permeable solutes in the luminal fluid retard fluid absorption by proximal tubules. This is an important consideration for understanding the actions of osmotic diuretics. 

The ability to produce a concentrated urine also matures over time. In the rat, this function is not mature until 2-3 weeks after birth. This is due to the lengthening of the loops of Henle and to maturation of ion transport function. Sodium influx from the renal tubular lumen stimulates proximal tubule growth and upregulates the expression of Na+K+-ATPase, the major transporter of sodium in the kidney, in the basolateral membranes of the epithelium. 

Proximal tubular secretion is an energy-dependent active-transport mechanism. Specific high-affinity proteins in the proximal tubule transport drugs into the tubule for elimination via the urine. These proteins can also remove acidic and basic drugs from plasma protein-binding sites and transport them into the tubule. Since it is carrier-mediated, this mechanism is a saturable system. Therefore, other drugs may also compete for transport where similar carriers are employed. 

Hexachlorobutadiene is a nephrotoxic industrial chemical, damaging the pars recta of the proximal tubule. Initial conjugation with GSH is necessary, followed by biliary secretion and catabolism resulting in a cysteine conjugate. The conjugate is reabsorbed and transported to the kidney where it can be concentrated and becomes a substrate for the enzyme p-lyase. This metabolizes it into a reactive thiol, which may react with proteins and other critical macro molecules with mitochondria as the ultimate target. The kidney is sensitive because the metabolite is concentrated by active uptake processes (e.g., OAT 1), which reabsorb the metabolite into the tubular cells. 

A second important factor affecting the kidneys sensitivity to chemicals is its ability to concentrate the tubular fluid and, as a consequence, as water and salts are removed, to concentrate any chemicals it contains. Thus a nontoxic concentration in the plasma may be converted to one that is toxic in the tubular fluid. The transport characteristics of the renal tubules also contribute to the delivery of potentially toxic concentrations of chemicals to the cells. If a chemical is actively secreted from the blood into the tubular fluid, it will accumulate initially within the cells of the proximal tubule or, if it is reabsorbed from the tubular fluid, it will pass into the cells in relatively high concentration. 

Sodium bicarbonate, sodium chloride, glucose, amino acids, and other organic solutes are reabsorbed via specific transport systems in the early proximal tubule. Water is reabsorbed passively so as to maintain nearly constant osmolality of proximal tubular fluid. As tubule fluid is processed along the length of the proximal tubule, the luminal concentrations of the solutes decrease relative to the concentration of inulin, an experimental marker that is neither secreted nor absorbed by renal tubules (Figure 15-2). Approximately 85% of the filtered sodium bicarbonate, 40% of the sodium chloride, 60% of the water, and virtually all of the filtered organic solutes are reabsorbed in the proximal tubule. 

Sodium bicarbonate reabsorption by the proximal tubule is initiated by the action of a Na+/H+ exchanger located in the luminal membrane of the proximal tubule epithelial cell (Figure 15-3). This transport system allows sodium to enter the cell from the tubular lumen in exchange for a proton from inside the cell. As in all portions of the nephron, Na+/K+ ATPase in the basolateral... 

As the filtrate flows into the descending limb of this loop, the NaCl concentration in the fluid surrounding the tubule increases by a factor of four, and osmotic processes cause water to be reabsorbed. At the same time, salts and metabolic products are secreted into the tubular fluid. In the ascending limb, in contrast, the tubular wall is nearly impermeable to water. Here, the epithelial cells contain molecular pumps that transport sodium and chloride from the tubular fluid into the space between the nephrons (the interstitium). These processes are accounted for in considerable detail in the spatially extended model developed by Holstein-Rathlou et al. [14]. In the present model, the reabsorption l rmh in the proximal tubule and the flow resistance Rum are treated as constants. Without affecting the composition much, the proximal tubule reabsorbs close to 60% of the ultrafiltrate produced by the glomerulus. 

Third, active transport processes within the proximal tubule may further raise the intracellular concentration of an actively transported toxicant. During active secretion and/or reabsorption, substrates generally accumulate in proximal tubular cells in much higher concentrations than present in either luminal fluid or peritubular blood. 

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