Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: EC:1.1.1.21 (aldose reductase)
 3,305 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

We have examined the effect of diabetes on sodium/myo-inositol cotransporter (SMIT) mRNA levels and myo-inositol content in the kidney to test the hypothesis that diabetes-induced changes in renal myo-inositol levels are due to the regulation of SMIT mRNA levels. In streptozotocin-induced diabetic rats, after 3, 7 and 28 days of diabetes, SMIT mRNA levels in the whole kidney were increased three to fivefold, and remained increased by about twofold after six months of diabetes. Insulin treatment of diabetic rats normalized blood glucose levels and prevented the increase in SMIT mRNA levels. Treating diabetic rats with sorbinil, an aldose reductase inhibitor, corrected the abnormal accumulation of sorbitol but had no effect on the diabetes-induced increase in renal SMIT mRNA levels. The regional distribution of SMIT mRNA from normal rats showed a relative abundance in cortex, outer medulla, and inner medulla of 1.0:3.4:7.0. After seven days of diabetes, the levels of SMIT mRNA and myo-inositol content were significantly increased only in the outer medulla. In situ hybridization studies revealed that SMIT mRNA in the outer medulla was predominately localized to the medullary thick ascending limbs of Henle's loop and was not localized to any specific cell in the inner medulla. This distribution pattern was unchanged in diabetic rats. These studies show that diabetes causes an increase in renal SMIT mRNA, which is primarily localized to the outer medulla. Accumulation of myo-inositol by the thick ascending limb of Henle's loop may account for most of the increase caused by diabetes.
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PMID:Localization and regulation of renal Na+/myo-inositol cotransporter in diabetic rats. 888 79

The effect of changes in medullary extracellular tonicity on mRNA expression for aldose reductase (AR), sorbitol dehydrogenase (SDH), Na+/Cl-/betaine (BGT) and Na+/myo-inositol (SMIT) cotransporter in different kidney zones was studied using Northern blot analysis and non-radioactive in situ hybridization in four groups of rats: controls, acute diuresis (the loop diuretic furosemide was administered), chronic diuresis (5 days of diuresis), and antidiuresis [5 days of diuresis followed by 24 h deamino-Cys1, d-Arg8 vasopressin (dDAVP)]. Acute administration of the loop diuretic furosemide significantly reduced AR, SMIT and BGT gene expression in the inner and outer medulla compared with controls. Administration of dDAVP to chronically diuretic rats raised the expression of these three mRNAs in the inner but not the outer medulla compared with the chronically diuretic rats. None of these alterations in medullary tonicity significantly changed SDH expression. The in situ hybridization studies showed AR, BGT and SMIT mRNAs to be expressed in both epithelial and non-epithelial cells of the outer and inner medulla. The various cell types (epithelial, endothelial and interstitial cells) differed in their expression pattern and intensity of AR, SDH, BGT and SMIT mRNA, but the inner medullary cells responded uniformly to a decrease in extracellular tonicity with a reduction, and to an increase with enhancement of their AR, BGT and SMIT expression.
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PMID:Expression of aldose reductase, sorbitol dehydrogenase and Na+/myo-inositol and Na+/Cl-/betaine transporter mRNAs in individual cells of the kidney during changes in the diuretic state. 992 66

Hypertonicity (most often present as high salinity) is stressful to the cells of virtually all organisms. Cells survive in a hypertonic environment by increasing the transcription of genes whose products catalyze cellular accumulation of compatible osmolytes. In mammals, the kidney medulla is normally hypertonic because of the urinary concentrating mechanism. Cellular accumulation of compatible osmolytes in the renal medulla is catalyzed by the sodium/myo-inositol cotransporter (SMIT), the sodium/chloride/betaine cotransporter, and aldose reductase (synthesis of sorbitol). The importance of compatible osmolytes is underscored by the necrotic injury of the renal medulla and subsequent renal failure that results from the inhibition of SMIT in vivo by administration of a specific inhibitor. Tonicity-responsive enhancers (TonE) play a key role in hypertonicity-induced transcriptional stimulation of SMIT, sodium/chloride/betaine cotransporter, and aldose reductase. We report the cDNA cloning of human TonE binding protein (TonEBP), a transcription factor that stimulates transcription through its binding to TonE sequences via a Rel-like DNA binding domain. Western blot and immunohistochemical analyses of cells cultured in hypertonic medium reveal that exposure to hypertonicity elicits slow activation of TonEBP, which is the result of an increase in TonEBP amount and translocation to the nucleus.
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PMID:Tonicity-responsive enhancer binding protein, a rel-like protein that stimulates transcription in response to hypertonicity. 1005 49

Cells exposed to hyperosmotic conditions maintain their volume by accumulating organic osmolytes. Taurine is considered as an osmolyte in brain cells. Accumulation of other osmolytes (sorbitol, myo-inositol and betaine), was shown in renal cells to result from an upregulation of the expression of the genes regulating osmolyte cell content. We have investigated the gene expression of the taurine transporter (TauT) and of the taurine biosynthetic enzymes, cysteine dioxygenase (CDO) and cysteine sulfinate decarboxylase (CSD) by measuring their mRNA levels in brain of salt-loaded rats. mRNA levels of genes previously identified as osmosensitive, namely aldose reductase (AR), myo-inositol transporter (SMIT) and betaine transporter (BGT1) were also determined. In whole brain, TauT-, SMIT- and BGT1-mRNA levels were significantly increased following acute salt-loading but SMIT-mRNA levels only remained elevated following chronic salt-loading while CDO-, CSD- and AR-mRNA levels remained unchanged in both conditions. Following acute salt-loading, mRNA levels of TauT, CDO, CSD, SMIT, BGT1 and AR were increased in cerebral cortex while SMIT- and BGT1-mRNA levels only were increased in striatum and habenula.TauT, CDO and CSD genes may be upregulated in brain of salt-loaded rats but the upregulation of the TauT gene appears more widespread. TauT, CDO and CSD are thus putative osmosensitive genes. However the actual pattern (amplitude, time course and regional occurrence) of the upregulation of each of the putative (TauT, CDO and CSD) and established (AR, SMIT and BGT1) osmosensitive genes differs markedly. This indicates that there exist other factors in brain cells which can selectively prevent the upregulation of these genes by hyperosmolarity.
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PMID:Gene expression of taurine transporter and taurine biosynthetic enzymes in brain of rats with acute or chronic hyperosmotic plasma. A comparative study with gene expression of myo-inositol transporter, betaine transporter and sorbitol biosynthetic enzyme. 1081 27

Sorbitol, myo-inositol, betaine, and taurine are held as organic osmolytes. When cells are exposed to a hyperosmotic medium, they accumulate these organic compounds and thus achieve osmotic equilibrium with the medium while maintaining their volume. In astrocyte primary cultures adapted to a chemically defined medium and then exposed to a medium made 30% hyperosmotic by adding sodium chloride or raffinose, we have comparatively investigated the expression of the genes encoding the proteins that control the cellular accumulation of these osmolytes, namely sorbitol biosynthetic enzyme, aldose reductase (AR), taurine biosynthetic enzymes, cysteine dioxygenase (CDO), and cysteine sulfinic acid decarboxylase (CSD), and the transporters of taurine (TauT), myo-inositol (SMIT), and betaine (BGT1) by assaying the corresponding mRNA levels through relative quantitative RT-PCR. When exposed to the hyperosmotic medium the astrocytes shrank rapidly and then slowly regained their initial volume after several hours. CDO- and CSD-mRNA remained unchanged, whereas AR-mRNA appeared increased only with the medium made hyperosmotic with sodium chloride. The mRNA levels of the transporters only showed significant and comparable increases in both hyperosmotic conditions. They were all significantly higher after 4-h exposure and back or close to normal values after 24-h exposure. The maximum level occurred at around 4 h (SMIT), 8 h (BGT1), and 12 h (TauT). The amplitude of BGT1-mRNA increase was much larger. When taurine was added to the hyperosmotic medium the cell volume recovery was greatly accelerated and the osmo-induced overexpression of TauT-, SMIT-, and BGT1-mRNA was fully prevented. The activation of the genes encoding the osmolyte transporters appears to be triggered when the cell shrinks below a certain volume threshold and prolonged once the cell volume has regained this threshold value most likely as a result of a marked inertia of the transducing pathway. Since the upregulation pattern of the transporters of the different osmolytes notably differs, we speculate that the activation threshold varies from one gene to another.
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PMID:Gene expression of the transporters and biosynthetic enzymes of the osmolytes in astrocyte primary cultures exposed to hyperosmotic conditions. 1100 16

Intracellular ionic strength may play an important role in regulating the expression of genes encoding osmolyte-accumulating molecules. To establish whether a strict relation exists between these variables, intracellular ionic strength (sum of Na+, Cl- and K+ concentrations) and the relative abundance of mRNA derived from various tonicity-sensitive genes was examined using electron microprobe analysis and Northern blots on primary cultures of rat papillary collecting duct (PCD) cells following acute or long-term alterations in medium tonicity. Hypertonic medium (450 mosmol kg(-1)) evoked an initial rise in intracellular ionic strength (269 +/- 5 vs. 194 +/- 7 mmol (kg wet weight (wt))(-1) in isotonic controls; means +/- S.E.M.), which subsequently declined gradually, and a significantly higher abundance of bgt1 (Na+- and Cl- -dependent betaine transporter), smit (Na+/myo-inositol cotransporter), ar (aldose reductase) and osp94 (osmotic stress protein 94) mRNAs. Conversely, exposure to hypotonic medium (200 mosmol kg(-1)) for 12 h was associated with significantly reduced intracellular ionic strength (153 +/- 4 mmol (kg wet wt)(-1)) and significantly reduced the abundance of smit and ar mRNAs. PCD cells preconditioned in hypotonic medium and re-exposed to isotonic medium showed significantly higher abundance of these mRNAs than isotonic controls, although the intracellular ionic strength did not differ. Two further tonicity-sensitive genes responded differently to medium tonicity: while the abundance of hsp70 (heat shock protein 70) mRNA increased significantly following both hypo- and hypertonic stress, inos (inducible nitric oxide synthase) mRNA abundance correlated inversely with medium tonicity. These findings support the view that the effect of intracellular ionic strength on the expression of bgt1, smit, ar and osp94 is modulated by additional factors such as cell volume, and that its effect on the pathways regulating hsp70 and inos is even more complex.
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PMID:Relationship between intracellular ionic strength and expression of tonicity-responsive genes in rat papillary collecting duct cells. 1218 Dec 87

TonEBP is a transcription factor that, when activated by hypertonicity, increases transcription of genes, including those involved in organic osmolyte accumulation. Surprisingly, it is expressed in virtually all tissues, including many never normally exposed to hypertonicity. We measured TonEBP mRNA (real-time PCR) and protein (Western blot analysis) in tissues of control (plasma osmolality 294 +/- 1 mosmol/kgH2O) and hyposmotic (dDAVP infusion plus water loading for 3 days, 241 +/- 2 mosmol/kgH2O) rats to test whether the ubiquitous expression of TonEBP mRNA is osmotically regulated around the normal plasma osmolality. TonEBP protein is reduced by hyposmolality in thymus and liver, but not in brain, and is not detected in heart and skeletal muscle. TonEBP mRNA decreases in brain and liver but is unchanged in other tissues. There are no general changes in mRNA of TonEBP-mediated genes: aldose reductase (AR) does not change in any tissue, betaine transporter (BGT1) decreases only in liver, taurine transporter (TauT) only in brain and thymus, and inositol transporter (SMIT) only in skeletal muscle and liver. Heat shock protein (Hsp)70-1 and Hsp70-2 mRNA increase greatly in most tissues, which cannot be attributed to decreased TonEBP activity. The conclusions are as follows: 1) TonEBP protein or mRNA expression is reduced by hyposmolality in thymus, liver, and brain. 2) TonEBP protein and mRNA expression are differentially regulated in some tissues. 3) Although AR, SMIT, BGT1, and TauT are regulated by TonEBP in renal medullary cells, other sources of regulation may predominate in other tissues. 4) TonEBP abundance and activity are regulated by factors other than tonicity in some tissues.
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PMID:Expression of osmotic stress-related genes in tissues of normal and hyposmotic rats. 1282 75

The transcription factor NFAT5/TonEBP, a member of the NFAT/Rel family of transcription factors, has been implicated in diverse cellular responses, including the response to osmotic stress, integrin-dependent cell migration, T cell activation, and the Ras pathway in Drosophila. To clarify the in vivo role of NFAT5, we generated NFAT5-null mice. Homozygous mutants were genetically underrepresented after embryonic day 14.5. Surviving mice manifested a progressive and profound atrophy of the kidney medulla with impaired activation of several osmoprotective genes, including those encoding aldose reductase, Na+/Cl--coupled betaine/gamma-aminobutyric acid transporter, and the Na+/myo-inositol cotransporter. The aldose reductase gene is controlled by a tonicity-responsive enhancer, which was refractory to hypertonic stress in fibroblasts lacking NFAT5, establishing this enhancer as a direct transcriptional target of NFAT5. Our findings demonstrate a central role for NFAT5 as a tonicity-responsive transcription factor required for kidney homeostasis and function.
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PMID:Loss of NFAT5 results in renal atrophy and lack of tonicity-responsive gene expression. 1498 20

The cells of the kidney medulla are exposed routinely to high extracellular concentrations of various solutes including NaCl, urea and ammonium (NH4+). Although it is well established that the expression of a variety of osmosensitive genes and proteins, which confer cytoprotection on renal medullary cells, is induced by high NaCl concentrations, the role of NH4+ in these cellular responses is unclear. This study thus addressed the effect of NH4+ on the expression of the betaine/GABA transporter (BGT-1), the sodium/myo-inositol cotransporter (SMIT), aldose reductase (AR), and heat shock protein 70 (HSP70) in Madin-Darby canine kidney (MDCK) cells, using Northern and Western blot analyses and enzyme-linked immunosorbent assay (ELISA). The incidence of apoptosis was monitored by determining caspase-3 activity and annexin V binding. Addition of NH4Cl (50 mM; total osmolality 400 mosmol (kg H2O)(-1) to the medium was more effective than equiosmolar NaCl in increasing BGT-1 and HSP70 mRNA abundance, but less effective in enhancing BGT-1 and HSP70 expression at the protein level. Qualitatively similar results were obtained for SMIT and AR mRNAs. Exposure to both isotonic and hypertonic, NH4Cl-containing medium enhanced apoptosis compared with equiosmolar, NaCl-containing media. These results suggest that, in addition to NaCl, NH4Cl may play a role in regulating the intracellular accumulation of organic osmolytes, the abundance of HSP70 and cell turnover in the renal medulla in vivo.
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PMID:Effect of ammonium on the expression of osmosensitive genes in Madin-Darby canine kidney cells. 1561 70

The cells of the renal medulla produce large amounts of prostaglandin E2 (PGE2) via cyclooxygenases (COX)-1 and -2. PGE2 is well known to play a critical role in salt and water balance and maintenance of medullary blood flow. Since renal medullary PGE2 production increases in antidiuresis, and since COX inhibition is associated with damage to the renal medulla during water deprivation, PGE2 may promote the adaptation of renal papillary cells to high interstitial solute concentrations. To address this question, MDCK cells were exposed to a gradual tonicity increase in the presence or absence of 20 microM PGE2 prior to analysis of (i) cell survival, (ii) expression of osmoprotective genes (AR, BGT1, SMIT, HSP70 and COX-2), (iii) subcellular TonEBP/NFAT5 abundance, (iv) TonEBP/NFAT5 transcriptional activity and (v) aldose reductase promoter activity. Cell survival and apoptotic indices after raising the medium tonicity improved markedly in the presence of PGE2. PGE2 significantly increased tonicity-mediated up-regulation of AR, SMIT and HSP70 mRNAs. However, neither nuclear abundance nor TonEBP/NFAT5-driven reporter activity were elevated by PGE2, but aldose reductase promoter activity was significantly increased by PGE2. Interestingly, tonicity-induced COX-2 expression and activity was also stimulated by PGE2, suggesting the existence of a positive feedback loop. These results demonstrate that the major medullary prostanoid, PGE2, stimulates the expression of osmoprotective genes and favours the adaptation of medullary cells to increasing interstitial tonicities, an effect that is not explained directly by the presence of TonEs in the promoter region of the respective target genes. These findings may be relevant in the pathophysiology of medullary damage associated with analgesic drugs.
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PMID:Prostaglandin E2 stimulates expression of osmoprotective genes in MDCK cells and promotes survival under hypertonic conditions. 1755 90


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