Kidney tubular transporters

Cross, R.J. and Taggart, J.L. (1950). Renal tubular transport Accumlation ofp-aminohippurate by rabbit kidney slices. Amer. J. Physiol. 161 181-190. 

As indicated earlier in this chapter, these transporter proteins are found in a variety of cell types but especially in those organs exposed to chemicals from the environment (e.g., gastrointestinal tract), excretory organs (e.g., kidney), and sensitive organs (e.g., brain). The proteins are usually found on the luminal side of epithelial cells in organs of exposure, such as the small intestine, which allows the cells to pump out the potentially hazardous chemical. In sensitive organs such as the brain, the transporters are on that side of cells that will allow chemicals to be pumped back into the blood or interstitial fluid. In organs of excretion, such as the kidney, the transporters are located on the apical side of cells such as the proximal convoluted tubular cells. 

The transporter has much lower activity in kidney [66], but the kinetic patterns are similar to those observed with liver mitochondria. Prevention of glutamate efflux from mitochondria by H" in kidney tubular cells is probably a very important aspect of control of ammoniagenesis in kidney (c.f.. Section 6.4). 

Van Crugten JT, Sallustio BC, Nation RL, Somogyi A. Renal tubular transport of morphine, morphine-6-glucuronide, and mor-phine-3-glucuronide in the isolated perfused rat kidney. Drug Metab Disp 1991 19 1087-1092. 

RennickB,ZiemniakJ, Smith l,TaylorM, Acara M. Tubular transport and metabolism ofcimetidine in chicken kidneys. Pharmacol ExpTher 1984 228 387-392. 

Limitations of the in vitro perfused juxtamedullary nephron preparation include 1) the availability of only a select population of juxtamedullary glomeruli near the inner surface of the kidney 2) underestimation of the contribution of flow in large vessels to preglomeru-lar resistance and 3) lack of characterization of tubular transport. 

Poola et al studied pentamidine toxicity in the isolated perfused rat kidney evaluating the effects of dosing and co-administration of tetraethylam-monium [150]. They also found that tubulotoxic-ity of pentamidine is dose-related and attributed to its degree of kidney sequestration caused by either the administration of a high dose of drug or by decreased tubular transport as caused by tetra-... 

Specific defects in particular functions of the nephrons can also be identified and evaluated. For example, assessment of the maximum concentrating capacity of the kidneys gives an estimate of antidiuretic hormone (ADH)-controUed reabsorption of solute-free water in the distal portion of the tubule. Pinpoint defects, caused by genetically determined deficiencies of specific tubular transport systems or ion channels and giving rise to characteristic biochemical disorders, are considered in Chapter 45. 

Many active transport processes are not directly driven by ATP hydrolysis but by ion gradients. For example, uptake of glucose or amino acids in enterocytes and kidney tubular cells is mediated by Na cotransport systems [6-9]. Na ions enter the cells along their electrochemical gradient, which is driven by the Na /K -ATPase (Figure 9.6). 

For example, some SLC on the sinusoidal (basolateral) membrane of hepatocytes take up organic anions, while the ABC on the apical membranes of bile canicular cells excrete them. The combined activities of these two transporters thus results in the vectorial transport of drugs from the blood to the bile. Similarly, the basolateral transporters of the kidney tubular cells act in a coordinated, vectorial manner with apical transporters to secrete organic cations (OCs) from the blood to the urine. 

Both the plasma membrane and internal membranes associated with organelles may be damaged by toxic compounds. As already discussed, this may be due to lipid peroxidation which alters and destroys membrane lipids. As many enzymes and transport processes are membrane bound this will affect the function of the organelle as well as the structure. Sulphydryl groups in membranes may be targets for mercuric ions in kidney tubular cells and for methyl mercury in the CNS for example. The result is changes in membrane permeability and transport and subsequent cell death. Structural damage can be... 

As noted previously, nucleosides and nucleoside analogs are used to treat HIV infection as well as certain types of cancers (Table 9.8). Many of these drugs are readily excreted by the kidney. Gonsequently, renal tubular transport of these hydrophilic compounds involves various transport systems. 

Boom, S.P.A. Moons, M.M. Russel, F.G.M. Renal tubular transport of cimetidine in the isolated perfused kidney of the rat. Drug Metab.Dispos., 1994, 22, 148—153... 

Hartnup disease Is another genetically determined and relatively rare autosomal recessive disorder. It is caused by a defect in the transport of neutral amino acids across both intestinal and renal epithelial cells. The signs and symptoms are, in part, caused by a deficiency of essential amino acids (see Clinical Comments). Cystinuria and Hartnup disease involve defects in two different transport proteins. In each case, the defect is present both in intestinal cells, causing malabsorption of the amino acids from the digestive products in the intestinal lumen and in kidney tubular cells, causing a decreased resorption of these amino acids from the glomerular filtrate. 

Roch-Ramel, F., F. White, L. Vowles, H.A. Simmonds, J.S. Cameron Micropuncture study of tubular transport of urate and PAH in the pig kidney. Am. J. Physiol. 239 (Renal Fluid Electrolyte Physiol. 8) F107-F112 (1980b). 

Pritchard JB, Miller DS (1992) Proximal tubular transport of organic anions and cations. In Seldin DW, Giebisch G (eds) The kidney physiology and pathophysiology, vol 2, 2nd edn. Raven, New York, p 2921 Rabinowitz MB, Kopple JD, Wetherill GW (1976) Kinetic analysis of lead metabolism in healthy humans. Clin Invest 90 700-706 Roels HA, Boeckx M, Ceulemans E, Lauwerys RR (1991) Urinary excretion of mercury after occupational exposure to mercury vapor and influence of the chelating agent meso-2,3-dimercaptosuccinic acid (DMSA). Br J Ind Med 48 247-253... 

In subsequent studies attempting to find a correlation of physicochemical properties and antimicrobial activity, other parameters have been employed, such as Hammett O values, electronic distribution calculated by molecular orbital methods, spectral characteristics, and hydrophobicity constants. No new insight on the role of physiochemical properties of the sulfonamides has resulted. Acid dissociation appears to play a predominant role, since it affects aqueous solubiUty, partition coefficient and transport across membranes, protein binding, tubular secretion, and reabsorption in the kidneys. An exhaustive discussion of these studies has been provided (10). 

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. 

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