Proximal convoluted tubule, transport

Quigley R, Chakravarty S, Zhao X, Imig JD, Capdevila JH (2009) Increased renal proximal convoluted tubule transport contributes to hypertensionin Cyp4al4 knockout mice. Nephron Physiol 113 p23-28... 

RJ Alpern. (1985). Mechanism of basolateralmembrane II -OH /IICOL transport in the rat proximal convoluted tubule. A sodium-coupled electrogenic process. J Gen Physiol 86 613-636. 

A nephron, showing the major sites and percentage (in braces) of sodium absorption along with other features of solute transport. The filtered load = GFR (180 L/day) Xplasma Na+ (140 mEq/L) or 25,200 mEq/day. About 1% of this amount is excreted in voided urine. Sites where tubular fluid is isosmotic, hypertonic, or hypotonic relative to plasma are shown. POT, proximal convoluted tubule LH, loop of Henle DOT, distal convoluted tubule CCD, cortical collecting duct TAL, thick ascending loop. 

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. 

Certain molecules, such as p-aminohippuric acid (Fig. 3.18), a metabolite of p-aminobenzoic acid are actively transported from the bloodstream into the tubules by a specific anion transport system. Organic anions and cations appear to be transported by separate transport systems located on the proximal convoluted tubule. Active transport is an energy-requiring process and therefore may be inhibited by metabolic inhibitors, and there may be competitive inhibition between endogenous and foreign compounds. For example, the competitive inhibition of the active excretion of uric acid by compounds such as probenecid may precipitate gout. 

At least seven different systems are known for transporting amino acids into cells. In the inherited disorder cystinuria, the carrier system responsible for reabsorption of the amino acids cysteine, ornithine, arginine, and lysine in the proximal convoluted tubule of the kidney is defective. The inability to reabsorb cystine leads to kidney stones. 

ALP activity is present in most organs of the body and is especially associated with membranes and cell surfaces located in the mucosa of the small intestine and proximal convoluted tubules of the kidney, in bone (osteoblasts), liver, and placenta. Although the precise metabolic function of the enzyme is not yet understood, it appears that ALP is associated with lipid transport in the intestine and with the calcification process in bone. 

The exact mechanism(s) responsible for fluoride s nephrotoxicity remain to be defined. The fluoride ion interferes with normal cell function on several levels. Fluoride is an inhibitor of several cellular enzyme systems and dirninishes tissue respiration and anaerobic glycolysis [89]. In the kidney, fluoride interferes with transport of sodium in the proximal convoluted tubule. It also inhibits adenylate cyclase in the collecting system and dirninishes the action of antidiuretic hormone. Experimental evidence in rats indicates that the chloride dependent pump, in the thick ascending part of Henle s loop, also is inhibited [90]. In human collecting duct cell cultures, exposure to fluoride ions inhib-... 

Tubular secretion of drugs occurs in the proximal convoluted tubule by active transport mechanisms normally used for the removal of waste products. Transport systems exist for the secretion of acidic substances, for example uric acid and basic substances, for example creatinine. Many drugs can be actively secreted by this mechanism, which increases their rate of removal from the body. 

Useful substances are reabsorbed from the kidney tubules back into plasma by diffusion or active transport. Much of this occurs early on in the nephron at the proximal convoluted tubule but also at the distal convoluted tubule where tubular filtrate concentration is high. Lipid-soluble drugs may be reabsorbed in this way and as a result, they are eliminated slowly from the body. Metabolism of drugs tends to make them less lipid soluble, more water soluble and therefore more likely to ionize. Tubular filtrate is normally slightly acid and this favours the excretion of basic drugs because they ionize more readily in acidic conditions and therefore do not diffuse easily back into plasma. 

Sulfonamide excretion occurs partly via the parent compounds in urine (most readily if urine pH is alkaline, as in herbivores), but predominantly through the less lipid-soluble and therefore more readily excreted metabolites described above. Some sulfonamides are also excreted via the active carrier-mediated transport system, which secretes organic acids from peritubular capillaries across proximal convoluted tubule cells and into tubular lumen fluid. Acetylated sulfonamides are usually less water-soluble than the parent compounds and are the main cause of the crystalluria that can occur, leading to tubular damage. Only small amounts are excreted in bile and milk. 

In the rabbit reabsorption occurred along the convoluted part, but net secretion along the pars recta of the proximal tubules (as proved by in vitro studies, Chonko et al., 1975, Schali and Roch-Ramel, 1980a). In the Dalmatian dog, a strain of dog which has a genetic defect in urate transport, no net movement of urate occurred in the proximal convoluted tubule and in the rabbit net secretion occurred into the pars recta (Roch-Ramel et al., 1976a). In the third species observed to secrete urate, the pig, in contrast, the convo-... 

In the rat, the Cebus monkey, and the mongrel dog it was shown that, along the proximal convoluted tubule, the reabsorptive movement is opposed by a secretory transport. In the dog (Roch-Ramel et al., 1976a) and in the Cebus monkey (Roch-Ramel and Weiner, 1975) the evidence is indirect, based on the decrease of urate delivery when pyrazinoic acid is given. 

In low-level chronic exposure, MX sequesters cadmium intracellularly as the cadmium-MT complex and thereby decreases the toxic effects of the metal. By contrast, extracellular cadmium-MX has been shown to be nephrotoxic to experimental animals. Parenteral injection of cadmium in the form of cadmium-MT can cause acute renal damage in rats and mice (Nordberg et al. 1975 Cherian et al. 1976 Squibb et al. 1984 Maitani et al. 1988). These toxic effects were similar to those observed after repeated exposure to cadmium salts but the critical renal concentration of cadmium is much lower after injection of cadmium-MX (10//g/g) than after repeated injections of cadmium salts (200//g/g). The low molecular weight cadmium-MX is freely filtered by the glomerulus and reabsorbed by the proximal convoluted tubules and can cause acute damage to the renal tubular epithelial cells (Cherian et al. 1976 Goyer et al. 1984 Dorian et al. 1992). It has been proposed that the hepatic cadmium-Mt is released and transported to kidney in blood plasma and that the nephrotoxicity occurs at a certain renal concentration of cadmium with chronic exposure (Goyer et al. 1978, 1984 Dudley et al. 1985). In a recent liver transplant experiment, the movement of cadmium-MX form liver to kidney was demonstrated in rats where the liver with cadmium-MX was transplanted to a control rat (Chan et al. 1993). 

Thiazides inhibit NaCI reabsorption from the luminal side of epithelial cells in the DCT by blocking the Na+/Q transporter (NCC). In contrast to the situation in the TAL, in which loop diuretics inhibit Ca2+ reabsorption, thiazides actually enhance Ca2+ reabsorption. This enhancement has been postulated to result from effects in both the proximal and distal convoluted tubules. In the proximal tubule, thiazide-induced volume depletion leads to enhanced Na+ and passive Ca2+ reabsorption. In the DCT, lowering of intracellular Na+ by thiazide-induced blockade of Na+ entry enhances Na+/Ca2+ exchange in the basolateral membrane (Figure 15-4), and increases overall reabsorption of Ca2+. Although thiazides rarely cause hypercalcemia as the result of this enhanced reabsorption, they can unmask hypercalcemia due to other causes (eg, hyperparathyroidism, carcinoma, sarcoidosis). Thiazides are useful in the treatment of kidney stones caused by hypercalciuria. 

Renal proximal tubular epithelium (e.g., convoluted tubules) reclaim protein, including immunoglobulin, from the urinary filtrate via sorting/recy-cling mechanisms in intracellular vesicles. The apical (lumen-facing) surface of these cells features a specialized brush border which expresses FcRn closely associated with (S2-microglobulin [110,116], Studies with cultured human renal proximal tubular epithelial cells have demonstrated bidirectional IgG transport and salvage by fully functional FcRn [110] as discussed further in the next section. 

Figure 10.1 Sites and mechanisms of action of diuretics. The location of each cell type along the nephron is indicated by the shading patterns. Spironoiactone (not shown) is a competitive aldosterone antagonist and acts primarily in the collecting duct. PT, proximal tubule LH, loop of Henie TAL, thick ascending limb DT, distal tubule DCT, distal convoluted tubule CD, collecting duct PC, principal cell CA, carbonic anhydrase CAI, carbonic anhydrase inhibitors , primary active transport. (Adapted with permission from Ellison D H 1991 The physiologic basis of diuretic synergism its role in treating diuretic resistance. Annals of Internal Medicine 114 886-894.)...

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