Membrane transport renal tubule

Bellemann, P. (1980). Primary monolayer culture of liver parenchymal cells and kidney cortical tubules as a useful new model for biochemical pharmacology and experimental toxicology. Studies in vitro on hepatic membrane transport, induction of liver enzymes, and adaptive changes in renal cortical enzymes. Arch. Toxicol. 44 63-84. 

Almost all diuretics exert their action at the luminal surface of the renal tubule cells. Their mechanism of action includes interaction with specific membrane transport proteins like thiazides, furosemide etc., osmotic effects which prevent the water permeable segments of the nephron from absorbing water like mannitol, and specific interaction with enzyme like carbonic anhydrase inhibitors i.e. acetazolamide, and hormone receptors in renal epithelial cells like spironolactone. 

This chapter is divided into three sections. The first section covers renal tubule transport mechanisms. The nephron is divided structurally and functionally into several segments (Figure 15-1, Table 15-1). Many diuretics exert their effects on specific membrane transport proteins in renal tubular epithelial cells. Other diuretics exert osmotic effects that prevent water reabsorption (mannitol), inhibit enzymes (acetazolamide), or interfere with hormone receptors in renal epithelial cells (aldosterone receptor blockers). The physiology of each segment is closely linked to the basic pharmacology of the drugs acting there, which is discussed in the second section. Finally, the clinical applications of diuretics are discussed in the third section. 

The Na+ gradient established by the (Na+, K+)-ATPase is utilized in the transport of a number of solutes into animal cells via Na-solute cotransport or symport.68 This is well known for glutamate. Renal Na+ cotransport systems for mono- and di-carboxylic acids and for various amino acids have been functionally reconstituted in proteoliposomes. These transport systems are polypeptides solubilized from brush border membranes of renal proximal tubules. The establishment of Na+ gradients (high Na+ outside) resulted in increases in concentrations of substrate inside the proteoliposomes.69... 

Mineralocorticoids are believed to increase sodium reabsorption by affecting sodium channels and sodium pumps on the epithelial cells lining the renal tubules.18,58 Mineralocorticoids ability to increase the expression of sodium channels is illustrated in Figure 29-5. These hormones enter the tubular epithelial cell, bind to receptors in the cell, and create an activated hormone-receptor complex.18 This complex then travels to the nucleus to initiate transcription of messenger RNA units, which are translated into specific membrane-related proteins.27,58 These proteins in some way either create or help open sodium pores on the cell membrane, thus allowing sodium to leave the tubule and enter the epithelial cell by passive diffusion.27,83 Sodium is then actively transported out of the cell and reabsorbed into the bloodstream. Water reabsorption is increased as water follows the sodium movement back into the bloodstream. As sodium is reabsorbed, potassium is secreted by a sodium-potassium exchange, thus increasing potassium excretion (see Fig. 29-5). 

One in vitro study on rat renal tissue homogenate showed barium weakly inhibited the sodium-potassium-adenosine triphosphatase enzyme system (Kramer et al. 1986). A second study on mouse kidney tubules showed barium chloride could depolarize the membrane and inhibit potassium transport (Volkl et al. 1987). A similar defect in cell membrane transport in humans could be responsible for the renal involvement observed in some cases of acute barium poisoning. 

Oatpla3 consists of two variants (Oat-kl and Oat-k2) in the kidney (69,70). Oat-k2 lacks 172 amino acids at the amino terminal (70). The localization of Oat-kl has been suggested to be brush border membrane of the renal tubules since polyclonal antibody detected Oat-kl only in the brush border membrane-enriched fraction from the kidney (71). In contrast to other Oatps, Oat-kl mediates facilitated transport since the uptake by Oat-kl was insensitive to an ATP depleter (sodium azide) (69). Oat-kl accepts only folate derivatives such as MTX and folate, while the substrates of Oat-k2 include TCA and prostaglandin E2 in addition to these folate derivatives (69,70). 

Imaoka T, Kusuhara H, Adachi-Akahane S, et al. The renal-specific transporter mediates facilitative transport of organic anions at the brush border membrane of mouse renal tubules. J Am Soc Nephrol 2004 15 2012-2022. 

Masuda S, Saito H, Nonoguchi H, et al. mRNA distribution and membrane localization of the OAT-K1 organic anion transporter in rat renal tubules. FEBS Lett 1997 407 127-131. 

Anzai N, Jutabha P, Enomoto A, et al. Functional characterization of rat organic anion transporter 5 (Slc22al9) at the apical membrane of renal proximal tubules. J Pharmacol Exp Ther 2005 315 534—544. 

In the kidney, filtered solutes such as glucose are recovered from the forming urine primarily by active transport mechanisms in the renal tubules. As in the small intestine, glucose is removed from the tubule lumen by SGLT1 and exits across the basolateral membrane via GLUT2. The low affinity of GLUT2 makes flow from the blood into the tubule epithelial cells minimal at normal blood glucose concen-... 

Second, certain nucleotide phosphonates (e.g., adefovir and cidofovir) are effective antivirals, but their use in the clinic is limited by renal toxicity. This is believed to be caused by avid uptake at the basolateral membrane of renal proximal tubule cells followed by slow transport into the urine at the apical membrane, a sequence of events that results in intracellular drug accumulation and thus toxicity. As with penicillin, the OAT family of transporters has been implicated in cidofovir uptake. Co-administration of probenecid with cidofovir has been shown to decrease renal clearance of the antiviral and reduce its nephrotoxicity, presumably through com-... 

Hartnup disorder is an autosomal recessive impairment of neutral amino acid transport affecting the kidney tubules and small intestine. It is believed that the defect is in a specific system responsible for neutral amino acid transport across the brush-border membrane of renal and intestinal epithelium, but the defect has not yet been characterised. 

Hartnup disease is a rare genetic condition in which there is a defect of the membrane transport mechanism for tryptophan and other large neutral amino acids. The result is that the intestinal absorption of free tryptophan is impaired, although dipeptide absorption is normal. There is a considerable urinary loss of tryptophan (and other amino acids) as a result of the failure of the normal reabsorption mechanism in the renal tubules - renal aminoaciduria. In addition to neurological signs that can be attributed to a deficit of tryptophan for the synthesis of serotonin in the central nervous system, the patients show clinical signs of pellagra, which respond to the administration of niacin. 

The major sites of regulation of Na balance are the principal cells of the renal tubule. The proteins involved in regulating salt balance include Na,K ATPase, the sodium channel, and the potassium channel. These proteins arc membrane-bound proteins. They are used for transporting Na and K across the membranes of the tubule cell. Sodium rcabsorption involves the transport of Na appearing in the lumen of the renal tubule into the tubule ceil and on through the cell to the interstitial space. The Na appearing in the interstitial space can then pass into the capillaries to enter the bloodstream. 

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