Evidence for coordinated induction and repression of ecto-5'-nucleotidase (CD73) and the A2a adenosine receptor in a human B cell line

In the human B cell line P493-6 two mitogenic signals, the EpsteinBarr virus nuclear antigen 2 (EBNA2) and myc, can be independently regulated by means of an estrogen receptor fusion construct or an inducible expression vector, respectively. Shut off of EBNA2, either in the presence or absence of myc, leads to a significant increase in enzymatic activity and surface expression of ecto-5nucleotidase (CD73) as well as an increased adenosine receptor response in cyclic AMP formation. Shut off of myc expression has a small additional positive effect on CD73 activity. Among the four different subtypes of adenosine receptors, the A2a receptor exclusively is subject to regulation in this system, which is substantiated by pharmacologic data (specific agonists and inhibitors), as well as on the mRNA level. With upregulated CD73 and A2a, cells also respond to 5AMP with increased cyclic AMP formation. Turn on of EBNA2 has the reverse effect of repression of CD73 and A2a expression. The time course of both induction and repression of CD73 and A2a is rather slow

Tubulointerstitial injury and the progression of chronic kidney disease

In chronic kidney disease (CKD), once injury from any number of disease processes reaches a threshold, there follows an apparently irreversible course toward decline in kidney function. The tubulointerstitium may play a key role in this common progression pathway. Direct injury, high metabolic demands, or stimuli from various other forms of renal dysfunction activate tubular cells. These, in turn, interact with interstitial tissue elements and inflammatory cells, causing further pathologic changes in the renal parenchyma. The tissue response to these changes thus generates a feed-forward loop of kidney injury and progressive loss of function. This article reviews the mechanisms of this negative cycle mediating CKD

Renal innervation plays no role in oxygen-dependent control of erythropoietin mRNA levels

To assess the role of renal innervation in O2-dependent control of erythropoietin (EPO) formation, we have determined EPO mRNA levels in both kidneys of unilaterally denervated rats and sham-operated controls using RNase protection. To investigate whether possible effects of renal nerve input are related to the type of hypoxic stimulus and the degree of stimulation, animals were studied under basal conditions, after exposure to normobaric hypoxia (8% O2, 4 h) or CO (0.1%, 4 h), and after acute hemorrhage (decrease in hematocrit from 40.8 +/- 0.5 to 12.7 +/- 0.5% within 7 h; mean +/- SE, n = 6). Serum EPO levels rose on average 22-, 49-, and 48-fold under the three stimuli and were unaffected by unilateral denervation. Renal EPO mRNA levels in unilaterally denervated animals, when expressed in arbitrary units revealed by comparison with an external standard, were 7.0 +/- 1.5 vs. 6.3 +/- 2.0 (normoxia), 432 +/- 136 vs. 451 +/- 156 (normobaric hypoxia), 971 +/- 93 vs. 930 +/- 120 (CO), and 604 +/- 170 vs. 689 +/- 203 (hemorrhagic anemia) in the intact vs. the denervated kidney (mean +/- SE, n = 3). Furthermore, there was no difference between EPO mRNA levels of either kidney of unilaterally denervated animals and levels in sham-operated controls. We conclude that renal nerve input plays no significant role in the control of the EPO gene under both basal and stimulated conditions

Influence of dietary NaCl intake on renin gene expression in the kidneys and adrenal glands of rats

The aim of this study was to examine the influence of dietary NaCl intake on renin gene expression in the kidneys and adrenal glands of adult rats. Rats were kept on low (0.02%, w/w), normal (0.6%) or high (4%) NaCl diets and plasma renin activity (PRA) and the relative abundance of renin messenger ribonucleic acid (mRNA) in renal and adrenal tissue were followed for 20 days. In animals on a normal-salt diet PRA and renal renin mRNA levels did not change with time. PRA values in animals on the low-salt diet increased transiently (about threefold) and then declined again during the third week of treatment. Renal renin mRNA levels in these animals paralleled the changes of PRA. Conversely, in the animals kept on a high-salt diet PRA values decreased transiently and renal renin mRNA decreased continuously to about 50% of control values. Arterial blood pressure measured in conscious animals was not significantly influenced by the different salt diets. To establish whether the changes in renin mRNA levels are mediated by renal nerve input, animals on the different diets were also studied after unilateral renal denervation. Renal nerve section led to a 50% decrease of renin mRNA levels in the denervated kidneys in animals kept on the normal-salt diet. In the animals on the low-salt diet renin mRNA rose to similar levels in the denervated to those in the innervated kidney, while in animals receiving a high-salt diet renin mRNA was further decreased in the denervated kidneys.(ABSTRACT TRUNCATED AT 250 WORDS

Cohesive sediment transport processes

The general aim of the Project ''Cohesive Sediment'' of the MAST programme ''G6 Coastal Morphodynamics'' is to advance the knowledge and modelling of physical processes related to cohesive sediment in coastal environments. Bette insights are given into deposition modelling, consolidation theories and associated constitutive relationships, laboratory experiments of liquefaction by waves only or combined waves and currents, modelling of flow-sediment interaction and turbulence in the water column, and the conduct of laboratory erosion experiments. Short term recordings of deposition events, wave effects, consolidation and bottom turbulence in muddy environments emphasise the distance which remains to be covered in order to understand and predict the processes in the field

The renal Na+/phosphate cotransporter NaPi-IIa is internalized via the receptor-mediated endocytic route in response to parathyroid hormone.

The major renal Na(+)/phosphate cotransporter, NaPi-IIa, is regulated by a number of factors including parathyroid hormone (PTH), dopamine, and dietary phosphate intake. PTH induces the acute internalization of NaPi-IIa from the brush border membrane (BBM) and its routing to and subsequent degradation in lysosomes. Previous work indicated that megalin, part of the apical receptor-mediated endocytic apparatus, may play a role in the PTH-induced removal of NaPi-IIa. Here we examined in rats the time-dependent internalization route of NaPi-IIa after acute PTH application using immunohistochemistry and markers of several endocytic compartments. NaPi-IIa removal from the BBM was detectable as early as 5 min after PTH injection. After 10-15 min, NaPi-IIa was localized in subapical compartments positive for clathrin. Shortly thereafter, NaPi-IIa appeared in endosomes stained for EEA1 (early endosomal antigen 1). After 45-60 min, NaPi-IIa was found in late endosomes/lysosomes marked with lgp120. In contrast, no change in the subcellular localization of megalin and the Na(+)/H(+) exchanger NHE3 was detected up to 60 min after PTH injection. To further characterize the internalization route, insulin, as a marker for receptor-mediated endocytosis, and horseradish peroxidase (HRP) and fluorescein isothiocyanate (FITC)-dextran (10 kDa), as markers for fluid-phase mediated endocytosis, were used. NaPi-IIa colocalized with insulin 5-30 min after PTH injection but did not overlap with HRP or FITC-dextran. These results demonstrate a distinct internalization route of NaPi-IIa in response to acute PTH application that may involve the receptor-mediated endocytic pathway including clathrin-coated vesicles and EEA1-positive early endosomes, and routes NaPi-IIa to lysosomes for degradation

Which factor mediates reno-renal control of renin gene expression?

The results suggest that the suppression of renin gene expression in the contralateral kidneys of stenosed kidneys is not due to compensatory renal growth nor mediated by systemic blood pressure, angiotensin II AT1 receptors or renal nerves. We therefore hypothesize that kidneys with reduced perfusion release a humoral factor that acts as a potent inhibitor of renin gene expression

Role of Interferon-Gamma in Interleukin 12-Induced Pathology in Mice

Interleukin 12 (IL-12) activates natural killer (NK) and T cells with the secondary synthesis and release of interferon-gamma (IFN-gamma) and other cytokines. IL-12-induced organ alterations are reported for mice and the pathogenetic role of IFN-gamma is investigated by the use of mice deficient in the IFN-gamma receptor (IFN-gamma R(-/-)). IL-12 caused a rapid infiltration of liver and splenic red pulp with activated macrophages; this and increased NK cells resulted in a fivefold increase of splenic weight in wild-type mice. Splenomegaly was associated with myelosuppression and decreasing peripheral leukocyte counts. IL-12-induced changes in wild-type mice were associated with markedly increased IFN-gamma serum levels and up-regulation of major histocompatibility complex (MHC) class I and II expression in various epithelia. IL-12 induced a qualitatively similar macrophage infiltration in IFN-gamma R(-/-) mice, less marked splenomegaly (to 2 x normal), and no MHC upregulation. Strikingly increased vascular endothelial intercellular adhesion molecule-1 expression was apparent in both IFN-gamma R(-/-) and IFN-gamma R(+/+) mice. Restricted to mutant mice was a severe, invariably lethal, interstitial, and perivascular pulmonary macrophage infiltration with diffuse pulmonary edema. Extensive quantitative reverse transcriptase polymerase chain reaction analysis revealed an increase of only IL-6 and IL-10 pulmonary gene transcripts in IFN-gamma R(-/-) mice compared with wild-type mice. IL-12-induced myelosuppression is due to IFN-gamma-release from NK cells and T cells, and is associated with macrophage activation and distinct MHC class I and II antigen upregulation. The pulmonary pathology in IFN-gamma R(-/-) mice, however, reveals a toxic potential for IL-12 and suggests that endogenous IFN-gamma plays a protective role in preventing fatal pulmonary disease in these mice