Renal epithelium

Figure 15.2 Transport proteins involved in the intestinal absorption and the renal and hepatic excretion of drugs. In the intestine, drugs are taken up from the luminal side into enterocytes before the subsequent elimination into blood. In hepatocytes, drugs are taken up from the blood over the basolateral membrane and excreted over the canalicular membrane into bile. In the renal epithelium, drugs undergo secretion (drugs are taken up from the blood and excreted into the urine) or reabsorption (drugs are taken up from the urine and are excreted back into blood). Uptake transporters belonging to the SLC transporter superfamily are shown in red and export pumps...

In the renal epithelium, many uptake transporters are localized in the basolateral membrane and efflux transporters are localized in the apical membrane (Figure 15.2). As a result, vectorial transport of endogenous substances and of drugs from the blood into the urine is achieved. The important uptake transporters are members of the SLC22 family of solute carriers, especially the family members OCT2 and OAT2, which are highly expressed in human kidney. 

The current studies were conducted in rodents with I/R ARE, an extensively investigated, albeit imperfect model of the most common and the most treatment-resistant type of clinical AKI. Morigi et al. (Morigi et al, 2004), using rodents with cisplatinum-induced ARE, showed that administration of MSC improved renal function, and MSC appeared to directly contribute to the reconstitution of renal epithelium by transdifferentiation. However, these investigators did not demonstrate that the observed transdifferentiation of MSC is the actual mechanism of renoprotection, and they presented no data regarding the actual numbers of donor cells that undertook the tubular repair. It may be... 

The alkylglycoside vector is a kidney-specific delivery system that has recently been established [23-25].This vector is efficiently taken up from the basal side of the renal epithelium in a blood flow-limited manner and it can be used with several types of therapeutic molecules. The following sections summarize and discuss, first, how the novel kidney-specific alkylglycoside vector was identified, second, its structural and size requirements and third, the potential limitations of delivery to the kidney and the characterization of its binding sites on kidney cell membranes. 

Dichloroacetylene inhalation induced nephrotoxic effects in rats and male rabbits including tubular and focal necrosis in the collecting tubules and increased mitotic activity in the renal epithelium. Hepatotoxic effects and neuropathological changes were also reported in male rabbits (lARC, 1986). 

Fujimoto S, Niisato N, Sugimoto T, Marunaka Y. 2005. Quercetin and NPPB-induced diminution of aldosterone action on Na + absorption and ENaC expression in renal epithelium. Biochem Biophys Res Commun 336 401-407. 

Mittal BV, Cotton RE. Severely atypical changes in renal epithelium in biopsy and graft nephrectomy specimens in two cases of cadaver renal transplantation. Histopathology 1987 11(8) 833-41. 

The loss of gate function of fhe renal tubular cells prevents the renal epithelium from acting as a barrier to free movement of solute and water across the tubular epithelium. Thus, "backleak" of glomerular... 

Cohen AH, Sun NCJ, ShapshakP, Imagawa DT. Demonstration of HIV in renal epithelium in HIVassociated nephropathy. Modern Path 1989 2 125-128. 

Thamiselvan S, Khan SR. Oxalate and calcium oxalate are injuriousto renal epithelium cells results of in vivo and in vitro studies. J.Pathol. 1998,-Suppl 1 66-9. 

UmekawaT, Chegini N, Khan SR. Oxalate ions and calcium oxalate crystals stimulate MCP-1 expression by renal epithelium cells. Kidney Int. 2002 61 105-12. 

The purpose of this chapter is to present overviews of a selection of the major endothelial and epithelial barriers to drug delivery for which there are either primary culture or cell line systems that recapitulate the characteristics of the in vivo barrier. Our objective is to define some general characteristics of cell culture models and highlight the more commonly applied primary cell cultures and cell lines in use today. Specifically, we focus on cell culture models for the intestinal epithelium, blood-brain barrier, pulmonary and nasal epithelium, ocular epithelium, placental barrier, and renal epithelium. Renal epithelium was included here primarily because some cell lines derived from this tissue [e.g., Madin-Darby canine kidney cells (MDCK)] are often used as surrogates for other barriers by pharmaceutical scientists. We have arbitrarily chosen to exclude the skin and liver from the scope of this overview. However, it should be noted that hepatocyte cell culture models, for example, are becoming more widely available and have been the subject of recent reviews.1,2... 

Vasopressin promotes increased resorption of water in the renal distal tubule by stimulating insertion of water channels or aquaporins into the apical membranes of kidney tubules. Water is resorbed across the renal epithelium into the blood leading to a decrease in plasma osmolarity and an increase in the osmolarity of urine. In DI, this process is impaired, leading to excessive urine production, hi the absence of vasopressin, the kidney cannot resorb water and it flows out as urine. This condition can arise from a deficiency in vasopressin secretion from the posterior pituitary as a result of hypothalamic tumors, injury (as in the case of this patient) or infection. Alternately,... 

Glahn RP, Van Campen D, Dousa TP. Aflatoxin B1 reduces Na(-l-)-P(i) co-transport in proximal renal epithelium studies in opossum kidney (OK) cells. Toxicology 1994 92 91-100. 

Enterohemorrhagic Escherichia coli (EHEC) 0157 H7 causes serious hemorrhagic colitis, thrombotic thrombocytopenic purpura, and hemolytic uremic syndrome in humans. Verotoxins produced by EHEC are the pathogens of these diseases. Two different verotoxins have been reported, VTl and VT2, that destroy mucosa and renal epithelium. The effect of macrolides at sub-MIC concentration was reported on the production of verotoxin (VT) by E. coli 0157. Nakata et al observed that the production of VTl was suppressed up to 10 hr when bacteria were incubated with 1/100 of MIC of CAM [83]. The production of VTl reached the control level after 22 hr even with 1/10 of MIC of CAM. On the other hand, production of VT2 was completely suppressed by 22 hr with 1/10 of MIC. This effect was observed when E. coli 0157 was incubated with EM. In contrast to the macrolides, ampicillin at sub-MIC levels did not inhibit the production of both VTl and VT2. To clarify the mechanism of suppression of VT production by macrolides, a macrolide-resistant gene of a S. pneumonia strain, the ermAM gene, encoding an enzyme of methylation of 23S RNA was transformed into an... 

Molecular and cellular organization of transepithelial calcium transport Calcium transport across the intestinal and renal epithelium proceeds on a transcellular as well as on a paracellular route. Transfer across polarized cells is a vectorial multi-step process (Bronner 1990, 1991), which encompasses (i) calcium entry across the brush-border membrane via two types of calcium channels (Muller et al. 2000, Peng etal. 2000, Slepchenko and Bronner 2001) ... 

As with glucose transport, the Na -dependent carriers of the apical membrane of the intestinal epithelial cells are also present in the renal epithelium. However, different isozymes are present in the cell membranes of other tissues. Conversely, the facilitated tiansport carriers in the serosal membrane of the intestinal epithelia are similar to those found in other cell types in the body. During starvation, the intestinal epithelia, like these other cells, take up amino acids from the blood to use as an energy source. Thus, amino acid transport across the serosal membrane is bidirectional. 

Amino acids that enter the blood are transported across cell membranes of the various tissues principally by Na -dependent cotransporters and, to a lesser extent, by facilitated transporters (Table 37.1). In this respect, amino acid transport differs from glucose transport, which is Na -dependent transport in the intestinal and renal epithelium but facilitated transport in other cell types. The Na dependence of amino acid transport in liver, muscle, and other tissues allows these cells to concentrate amino acids from the blood. These transport proteins have a different genetic basis, amino acid composition, and somewhat different specificity than those in the luminal membrane of intestinal epithelia. They also differ somewhat between tissues. For instance, the N system for glntamine nptake is present in the liver bnt either not present in other tissues or present as an isoform with different properties. There is also some overlap in specificity of the transport proteins, with most amino acids being transported by more than one carrier. 

The kidneys are frequent targets for and exhibit adverse effects from many drugs and toxic chemicals due to their physiological functions and structure. In terms of function, the renal epithelium is exposed to any chemical in the blood by virtue of both glomerular filtration and secretion from the nearby renal circulation. A critical fact that emphasizes the unique physiology of the kidneys is that they typically comprise <1% of total body weight yet receive 20-25% of cardiac output. Hence, the kidneys are disproportionately exposed to chemicals in the blood. 

A further unsolved problem is the predisposition of the media of blood vessels, ganglion cells, renal epithelium and reticuloendothelial system for accumulation of the lipid. This may be related to the function of the stored material or of some material associated with it or else may result from its physical properties, particularly its solubility. In the case of the kidney, impaired excretion of these glyco-lipids may be the cause of storage. 

---