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At least 19 recordsLinked to original sources
PubMed1996

Mesenchyme to epithelium transition during development of the mammalian kidney tubule.

Kidney epithelia have two separate origins. Collecting ducts develop in the manner of most glandular organs, by growth and branching of a bud derived from a pre-existing epithelium. Excretory tubules develop by a direct mesenchyme to epithelium transition (MET), which is induced by the tips of the developing collecting duct system as it invades a specialised area of mesenchymal cells. The process by which these metanephrogenic mesenchyme cells achieve MET can be divided into several stages; induction, acquisition of stem cell character, fate determination, condensation, epitheliogenesis, polarisation and maturation. Progress through these stages is regulated by 'checkpoints' at which permission to proceed requires specific signals. The stages of development are characterised by the expression of new combinations of genes that code for transcription factors (Hox genes, Pax genes, zinc finger proteins), signalling effectors (growth factors, Wnts, receptor tyrosine kinases) and morphoregulatory molecules (CAMs, cadherins, extracellular matrix ligands). This review summarises current knowledge about the molecular interactions that control MET in the kidney, and also about how their failure might result in Wilms' tumour, one of the most common cancers of childhood.

Animals↗
PubMed1996

Intercellular adhesion molecule-1 is necessary but not sufficient to activate CD4+ T cells. Discovery of a novel costimulator on kidney tubule cells.

Kidney tubule cells (KTC) are targets of T lymphocyte injury during allograft rejection and interstitial nephritis. KTC process and present self- and foreign Ags for immune recognition by CD4+ T cells in vivo and in vitro. However, it is not known whether KTC can provide the costimulatory signal required to fully activate CD4+ T cells. Using the MRL/MpJ fas model of lupus interstitial nephritis, we found that KTC did not express the costimulators B7-1 or B7-2. Nevertheless, KTC from both normal and systemically infected mice provided non-B7 costimulation to splenic CD4+ T cells. T cell proliferation was blocked by mAbs binding intercellular adhesion molecule-1 (ICAM-1) but not by mAb or fusion proteins binding B7-1, B7-2, heat-stable Ag, or vascular cell adhesion molecule-1. Importantly, ICAM-1 expression was necessary but not sufficient to provide costimulation. The transformed KTC line D3.B7- expressed high levels of ICAM-1 but did not provide costimulation. Interestingly, KTC provided costimulation to splenic T cells but not to a Th1 clone. These results show that freshly isolated KTC can provide non-B7 costimulation to splenic T cells via an unidentified costimulator and ICAM-1. Furthermore, these experiments demonstrate the complex nature of T cell activation and show that at least for splenic T cells, three or more signals may be required for full activation on live APC.

Animals↗
PubMed1989

An incubation system for the NMR study of kidney tubules.

Isolated kidney cortical tubules require a very rapid oxygen supply and mechanical agitation to be optimally functional. A sample chamber in which a tubule suspension is oxygenated by recirculating oxygen gas inside a coil of dialysis fibers to avoid cell loss through bubbling and in which the tubules are agitated by a gas-driven turbine has been designed. In such a system, dog cortical tubules (35-45 mg/ml) were found to be metabolically stable for more than 3 h as indicated by linear lactate consumption and glucose production. Small pH variations resulting from carbon dioxide and bicarbonate productions were measured. Good-quality 23Na NMR spectra of dog kidney cortical tubules were recorded with such a system, allowing a 1-min time resolution.

Animals↗
PubMed1979

Nephrotoxicity of aminophenols: effects of 4-dimethylaminophenol on isolated rat kidney tubules.

In isolated rat kidney tubules DMAP was found to inhibit the gluconeogenesis from lactate, pyruvate, or dihydroxyacetone. The ratio DMAP/protein rather than the calculated concentration of DMAP determined the strength of the effect, 20--25 nmoles DMAP/mg protein inhibiting the rate of gluconeogenesis by about 50%. The inhibition was not reversible. Phenacetin, 4-aminophenol and 4-acetamidophenol were much less effective than DMAP in inhibiting gluconeogenesis in isolated rat kidney tubules. DMAP 14C-labeled in the ring was quickly bound to proteins in kidney tubules. A portion of DMAP which did not exceed about 4 nmoles/mg protein, was bound in compounds soluble in perchloric acid. From this portion tris-GS-DMAP was isolated. DMAP diminished the glutathione content of isolated rat kidney tubules. Reduced glutathione added before DMAP prevented the inhibition of gluconeogenesis and diminished the binding of DMAP to proteins. The binding of DMAP required oxygen and was inhibited by carbon monoxide or cyanide. Several enzymes from isolated kidney tubules were found to be inhibited by DMAP doses which inhibited gluconeogenesis. Large DMAP doses also diminished the sums of ATP + ADP + AMP as well as NAD + NADH and NADP + NADPH. This effect corresponded to an increase in nucleotide degradation products and to increased activity of extracellular LDH. The results indicate that the inhibition of gluconeogenesis by DMAP is not due to a specific effect on one enzyme or on membranes but to unspecific reactions with many substances.

Aminophenols↗
PubMed1985

The effect of streptozotocin diabetes on insulin binding by isolated rat kidney tubules.

Preparations of kidney tubules were isolated from rat kidney cortex and were demonstrated to possess specific binding sites for insulin. The binding was time-and temperature-dependent and the label was displaced by bovine insulin, A1-B29 dodecoyl insulin, proinsulin and insulin A- and B-chains in proportion to their relative activity. Cell-associated degradation was studied by incubating tubules in the presence of fatty-acid-free albumin. The tubules showed high insulin-degrading activity, which was dependent on temperature, time and cell concentration. The number and affinity of insulin receptors on tubules isolated from kidneys taken from streptozotocin-diabetic rats was not significantly different from tubules isolated from untreated control or insulin-treated diabetic rats. Diabetes did not alter the kinetics of insulin degradation by the tubules. This lack of response by the tubules to changes in the concentration of circulating insulin supports the hypothesis that the kidneys do not play an active role in modulating the rate of insulin removal from the circulation.

Animals↗
PubMed1991

Concomitant synthesis and degradation of glutamine in isolated rabbit kidney tubules.

When rabbit kidney tubules were incubated with 1 mM [1-14C]glutamine as substrate, a release of 14CO2 together with a net production of glutamine were observed. That glutamine utilization was masked by higher rates of concomitant glutamine synthesis was demonstrated by: (i) inhibiting glutamine synthesis; and (ii) measuring the specific radioactivity of [1-14C]glutamine which fell during incubation.

Animals↗
PubMed1983

Metabolic heterogeneity of the proximal and distal kidney tubules.

Proximal and distal tubule suspensions were prepared from kidneys of Sprague-Dawley rats by an isolation procedure on a Percoll gradient. The marker enzymes alkaline phosphatase (brush border) and hexokinase (cytoplasmic) as well as p-aminohippurate transport capacity, gluconeogenic activity and electron microscopy were used to characterize the two kidney tubule suspensions. The results of this study indicate that cytochrome P-450 is localized to the proximal tubular cells and that the O-deethylation of 7-ethoxycoumarin was higher in the proximal than distal fraction. Both proximal and distal tubules showed glucuronidation and deacetylation capacities and a relatively equal distribution of non-protein sulfhydryls. These studies demonstrate metabolic heterogeneity of the nephron, the proximal tubule being the main site of renal xenobiotic metabolism. Understanding of metabolic heterogeneity of proximal and distal kidney tubules should provide important information regarding cell specific mechanisms of nephrotoxicity.

7-Alkoxycoumarin O-Dealkylase↗
PubMed1975

A morphometric study of cellular autophagy including diurnal variations in kidney tubules of normal rats.

Cellular autophagy in convoluted tubules of kidney was studied in 24 rats, killed in pairs at constant time intervals during one diurnal cycle, by (a) morphometric evaluation of tubular cells by the point-counting method in randomly sampled micrographs, and (b) selective search for autophagic vacuoles (AV) directly on the electron microscopy screen. The total area of tubular cells recorded in the electron microscopy sections was 93 X 10(-4) mum2. Since the distal convoluted tubules, covering about 12% of the whole tubulocellular area, contained only 3-4% of all AV, they were omitted from the main calculations. The number of AV per area unit and the total amount of segregated material showed a distinct diurnal rhythm, synchronous for the different types of AV which were distinguished from each other according to their contents. The minimum was found during the night, the maximum during the day. This rhythm appears similar to that described elsewhere in liver cells. The mean segregated fractions were calculated from the relation of segregated to nonsegregated material in proximal convoluted tubular cells. The segregated fraction of the mitochondria was 4.4 X 10(-4). This value could account for the degradation of all mitochondria in a cell within 15 days, i.e., the upper limit of the lifetime of mitochondrial DNA in the cortex of the kidney, if one assumes that a mitochondrion is destroyed within 10 min after being segregated. The degregated fraction of microbodies was 11.7 X 10(-4). This suggests a shorter lifetime of these organelles. It is concluded that cellular autophagy plays a significant role in the turnover of cytoplasmic constituents, including the membranes of the endoplasmic reticulum.

Animals↗
PubMed1996

Advantages and limitations of the use of isolated kidney tubules in pharmacotoxicology.

Among the cellular models used in in vitro renal pharmacotoxicology, isolated kidney tubules, used as suspensions mainly of proximal tubules, offer important advantages. They can be prepared in large amounts under nonsterile conditions within 1-2 h; thus, it is possible to employ a great number of experimental conditions simultaneously and to obtain rapidly many experimental results. Kidney tubules can be prepared from the kidney of many animal species and also from the human kidney; given the very limited availability of healthy human renal tissue, it is therefore possible to choose the most appropriate species for the study of a particular problem encountered in man. Kidney tubules can be used for screening and prevention of nephrotoxic effects and to identify their mechanisms as well as to study the renal metabolism of xenobiotics. When compared with cultured renal cell, a major advantage of kidney tubules is that they remain differentiated. The main limitations of the use of kidney tubules in pharmacotoxicology are (1) the necessity to prepare them as soon as the renal tissue sample is obtained; (2) their limited viability, which is restricted to 2-3 h; (3) the inability to expose them chronically to a potential nephrotoxic drug; (4) the inability to study transepithelial transport; and (5) the uncertainty in the extrapolation to man of the results obtained using animal kidney tubules. These advantages and limitations of the use of human and animal kidney tubules in pharmacotoxicology are illustrated mainly by the results of experiments performed with valproate, an antiepileptic and moderately hyperammonemic agent. The fact that kidney tubules, unlike cultured renal cells, retain key metabolic properties is also shown to be of the utmost importance in detecting certain nephrotoxic effects.

Animals↗
PubMed1977

Contribution of pH-sensitive metabolic processes to pH homeostasis in isolated rat kidney tubules.

The metabolism of isolated rat kidney tubules suspended in calcium-free physiological saline buffered with phosphate was found to be sensitive to changes in the pH of the suspending medium. Lowering the pH from 7.8 to 6.4 brought about increases in the rates of oxidation of added succinate, glutamate or glutamine as well as in the production of glucose from lactate, glutamine, succinate and fructose. The cellular ATP level was also higher in tubules incubated at pH 6.4 In contrast, the utilization of added glucose was greater at pH 7.8 than at pH 6.4, a substantial amount of lactate being produced at the higher pH. When glucose and either lactate or glutamine were provided as co-substrates glucose was the preferred fuel at pH 7.8 but the alternative substrate was the more readily utilized at pH 6.4. As a consequence of the metabolic activities of the tubules the pH of the suspending medium changed, utilization of lactate, glutamate or glutamine causing a rise in pH while conversion of glucose to lactate caused a fall in pH. In cases where two substrates were metabolized concurrently over a period of 3 h the extracellular pH tended towards a plateau level of approximately pH 7.4. It is proposed that pH-sensitive metabolism in isolated kidney tubules contributes to pH homeostasis in the cellular environment.

Adenosine Triphosphate↗
PubMed1995

Association of malachite green-positive material with heparan sulfate proteoglycan double tracks in basement membrane of mouse kidney tubules.

The presence of lipids in the basement membrane of the mouse kidney tubules was examined by histochemical staining with malachite green. Pieces of mouse kidney cortex were immersed in a fixative containing 3% glutaraldehyde and 0.1% malachite green in 0.067 M sodium cacodylate buffer, pH 6.8, for 18 hr at 4 degrees C. Control tissue was fixed in the same way except that no malachite green was added to the fixative. The tissue pieces were cryoprotected, frozen in Freon 22, and subjected to freeze-substitution in dry acetone containing 1% OsO4. Thin sections of Epon-embedded specimens were observed by electron microscopy at first without uranyl-lead counterstaining. The basement membrane of mouse kidney tubules was positively stained in a pattern composed of an irregular assembly of 5-8-nm wide strands. The nature of these malachite green-positive strands was further examined by counterstaining thin sections with uranyl-lead, and they were identified as 4.5-5-nm wide ribbon-like "double tracks" previously characterized as the form taken by heparan sulfate proteoglycan in basement membranes. It is concluded that lipids are present in the basement membrane of mouse kidney tubules in association with heparan sulfate proteoglycan.

Animals↗
PubMed1985

Iron delivery during proliferation and differentiation of kidney tubules.

Proliferation during kidney development can be stimulated with an iron chelator, ferric pyridoxal isonicotinoyl hydrazone (FePIH). Neither the starting products nor the intermediary in FePIH synthesis stimulated proliferation. Thus, the growth-promoting effects of FePIH are due to the iron ion. Some other low molecular weight, saturated iron chelators such as glycyl-histidyl-lysine acetate, nitrilotriacetic acid, ascorbate, citrate, and unchelated ferrous sulfate could not support as high a degree of proliferation as FePIH or transferrin. FePIH delivered just slightly less radioactive iron into the trichloroacetic acid-precipitable fraction than transferrin. The octanol/saline partition coefficients of radioactive iron in solution with transferrin, nitrilotriacetic acid, or chloride were all less than 0.06. Thus, these compounds cannot efficiently traverse the lipid membrane. On the other hand, Fe3+ carried by PIH had a partition coefficient of 0.96. Hence, FePIH can stimulate proliferation because it can carry iron through the lipid membrane. Transferrin is not lipophilic but it delivers iron by receptor-mediated endocytosis.

Animals↗
PubMed1978

Metabolic inhibitors and kidney tubule induction.

The induction of kidney tubules in metanephric mesenchyme has previously been shown to require close contact between the interacting tissues. In our study we show that low concentrations of inhibitors of RNA, DNA and protein synthesis inhibit tubule induction, although they do not seem to prevent the formation of contacts between the interacting tissues. The effective concentrations were about the same as those which inhibited the synthesis of macromolecules. Cycloheximide caused an increased synthesis of RNA. Low concentrations of Mitomycin C inhibited DNA synthesis but not tubule formation. A concentration of the inhibitors which caused weakened induction also caused a marked decrease in leucine incorporation. We concluded therefore, that a decrease in protein synthesis in the inducing tissue is responsible for the inhibition of induction.

Animals↗
PubMed1995

Induction of early stages of kidney tubule differentiation by lithium ions.

Kidney tubules develop by a mesenchyme-epithelium transition, normally induced by ureteric bud through a mechanism that remains obscure. Murine nephrogenesis in vitro has always required heterologous inducing cells. We have discovered that Li+ can elicit the early stages of epithelial differentiation in isolated nephrogenic mesenchyme. We have made detailed comparisons of the timing of morphoregulatory molecule expression between Li(+)-mediated induction and the traditional in vitro method using induction by spinal cord. Both followed the same program of early morphoregulatory molecule expression, though Li(+)-induced samples failed to progress into the later parts of the nephrogenic process. Mesenchymes induced by Li+ showed more DNA synthesis than controls, though less than those induced by spinal cord. Discovery of a chemical means to activate differentiation in the absence of heterologous tissue offers a new basis for studying molecular mechanisms regulating the early events of nephrogenesis, as well as for investigating transduction of inductive signals that initiate the process.

Animals↗
PubMed1990

Early expression of desmosomal components during kidney tubule morphogenesis in human and murine embryos.

Developing kidneys of human and murine fetuses have been stained with monoclonal antibodies to desmosomal proteins 1 and 2 (desmoplakins) (dp 1&2), desmosomal glycoprotein 1 (desmoglein) and a polyclonal antiserum to desmosomal glycoproteins 2 and 3 (desmocollins). All three antibodies stain the mesenchymal condensates that represent the first stage in kidney tubule development, indicating that desmosomal antigens are expressed very early in tubule morphogenesis. Desmosomal antigens are continuously expressed throughout the developing tubule being concentrated at the apical and basal regions of the lateral membranes of cells. Staining is also present in both visceral and parietal membranes of the developing Bowman's capsule. In the mature tubule, desmosomal staining becomes restricted to a discontinuous apico-lateral ring around the cells. Staining is completely lost from the visceral membrane of the mature Bowman's capsule (the podocytes) but persists in the parietal membrane. At the condensate stage, staining for dp1&2 is much more intense than staining for simple epithelial keratin. Electron microscopy showed the presence of small (ca 0.1 microns) punctate junctions in the developing tubule. These may be immature desmosomes. No fully mature desmosomes such as are present in mature kidney were found. The results suggest that desmosomal proteins and glycoproteins are involved in the early development of adhesive contacts between cells of the kidney tubule. The changing pattern of antigen expression, the loss of desmosomal staining from the podocytes and the immaturity of junctions suggest that desmosomal adhesion is labile during tubule morphogenesis, perhaps in order to facilitate changes of cell-cell contact.

Animals↗