The Experts below are selected from a list of 321 Experts worldwide ranked by ideXlab platform
Moo H Kwon - One of the best experts on this subject based on the ideXlab platform.
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Tonicity independent regulation of the osmosensitive transcription factor tonebp nfat5
American Journal of Physiology-cell Physiology, 2012Co-Authors: Julia A Halterman, Moo H Kwon, Brian R WamhoffAbstract:Tonicity-responsive enhancer binding protein (TonEBP/nuclear factor of activated T-cells 5 [NFAT5]) is a Rel homology transcription factor classically known for its osmosensitive role in regulating cellular homeostasis during states of hypo- and hypertonic stress. A recently growing body of research indicates that TonEBP is not solely regulated by Tonicity, but that it can be stimulated by various Tonicity-independent mechanisms in both hypertonic and isotonic tissues. Physiological and pathophysiological stimuli such as cytokines, growth factors, receptor and integrin activation, contractile agonists, ions, and reactive oxygen species have been implicated in the positive regulation of TonEBP expression and activity in diverse cell types. These new data demonstrate that Tonicity-independent stimulation of TonEBP is critical for tissue-specific functions like enhanced cell survival, migration, proliferation, vascular remodeling, carcinoma invasion, and angiogenesis. Continuing research will provide a better understanding as to how these and other alternative TonEBP stimuli regulate gene expression in both health and disease.
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downregulation of renal sodium transporters and Tonicity responsive enhancer binding protein by long term treatment with cyclosporin a
Journal of The American Society of Nephrology, 2007Co-Authors: Mee Rie Sheen, Un Sil Jeon, Chul Woo Yang, Moo H KwonAbstract:Tonicity-responsive enhancer binding protein (TonEBP) is a transcriptional activator that is regulated by ambient Tonicity. TonEBP protects the renal medulla from the deleterious effects of hyperosmolality and regulates the urinary concentration by stimulating aquaporin-2 and urea transporters. The therapeutic use of cyclosporin A (CsA) is limited by nephrotoxicity that is manifested by reduced GFR, fibrosis, and tubular defects, including reduced urinary concentration. It was reported recently that long-term CsA treatment was associated with decreased renal expression of TonEBP target genes, including aquaporin-2, urea transporter, and aldose reductase. This study tested the hypothesis that long-term CsA treatment reduces the salinity/ Tonicity of the renal medullary interstitium as a result of inhibition of active sodium transporters, leading to downregulation of TonEBP. CsA treatment for 7 d did not affect TonEBP or renal function. Whereas expression of sodium transporters was altered, the medullary Tonicity seemed unchanged. Conversely, 28 d of CsA treatment led to downregulation of TonEBP and overt nephrotoxicity. The downregulation of TonEBP involved reduced expression, cytoplasmic shift, and reduced transcription of its target genes. This was associated with reduced expression of active sodium transporters—sodium/potassium/ chloride transporter type 2 (NKCC2), sodium/chloride transporter, and Na,K-ATPase—along with increased sodium excretion and reduced urinary concentration. Infusion of vasopressin restored the expression of NKCC2 in the outer medulla as well as the expression and the activity of TonEBP. It is concluded that the downregulation of TonEBP in the setting of long-term CsA administration is secondary to the reduced Tonicity of the renal medullary interstitium.
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transcriptional regulation by changes in Tonicity
Kidney International, 2001Co-Authors: Joseph S Handler, Moo H KwonAbstract:Transcriptional regulation by changes in Tonicity. Most organisms respond to a hypertonic environment by accumulating small organic solutes. In contrast to high concentrations of electrolytes, the small organic solutes do not perturb the activity of enzymes and other macromolecules within the cell. When the renal medulla becomes hypertonic during antidiuresis, multiple signaling pathways are activated. Here, we review the role of Tonicity responsive enhancers (TonE) binding protein (TonEBP), a transcription factor activated in hypertonic cells. The activation of TonEBP by hyperTonicity results from its translocation to the nucleus as well as an increase in TonEBP mRNA and protein. TonEBP may have a role beyond the response to Tonicity since it is highly expressed in activated lymphocytes and in developing tissues.
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bidirectional regulation of Tonicity responsive enhancer binding protein in response to changes in Tonicity
American Journal of Physiology-renal Physiology, 2000Co-Authors: Stephen C Dahl, Joseph S Handler, Moo H KwonAbstract:Tonicity-responsive enhancer binding protein (TonEBP) regulates transcription of Tonicity responsive genes such as the sodium-myo-inositol cotransporter (SMIT), the sodium-chloride-betaine cotransp...
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nuclear redistribution of Tonicity responsive enhancer binding protein requires proteasome activity
American Journal of Physiology-cell Physiology, 2000Co-Authors: Djikolngar Maouyo, Joseph S Handler, Moo H KwonAbstract:Tonicity-responsive enhancer binding protein (TonEBP) is the transcription factor that regulates Tonicity-responsive expression of the genes for the sodium-myo-inositol cotransporter (SMIT) and the...
Joseph S Handler - One of the best experts on this subject based on the ideXlab platform.
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transcriptional regulation by changes in Tonicity
Kidney International, 2001Co-Authors: Joseph S Handler, Moo H KwonAbstract:Transcriptional regulation by changes in Tonicity. Most organisms respond to a hypertonic environment by accumulating small organic solutes. In contrast to high concentrations of electrolytes, the small organic solutes do not perturb the activity of enzymes and other macromolecules within the cell. When the renal medulla becomes hypertonic during antidiuresis, multiple signaling pathways are activated. Here, we review the role of Tonicity responsive enhancers (TonE) binding protein (TonEBP), a transcription factor activated in hypertonic cells. The activation of TonEBP by hyperTonicity results from its translocation to the nucleus as well as an increase in TonEBP mRNA and protein. TonEBP may have a role beyond the response to Tonicity since it is highly expressed in activated lymphocytes and in developing tissues.
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bidirectional regulation of Tonicity responsive enhancer binding protein in response to changes in Tonicity
American Journal of Physiology-renal Physiology, 2000Co-Authors: Stephen C Dahl, Joseph S Handler, Moo H KwonAbstract:Tonicity-responsive enhancer binding protein (TonEBP) regulates transcription of Tonicity responsive genes such as the sodium-myo-inositol cotransporter (SMIT), the sodium-chloride-betaine cotransp...
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Bidirectional regulation of Tonicity-responsive enhancer binding protein in response to changes in Tonicity
American Journal of Physiology-renal Physiology, 2000Co-Authors: Stephen C Dahl, Joseph S Handler, H. Moo KwonAbstract:Tonicity-responsive enhancer binding protein (TonEBP) regulates transcription of Tonicity responsive genes such as the sodium-myo-inositol cotransporter (SMIT), the sodium-chloride-betaine cotransporter (BGT1), and aldose reductase (AR). To characterize signals that activate TonEBP in Madin-Darby canine kidney (MDCK) cells, the abundance and nuclear distribution of TonEBP were studied after the osmolality of the culture medium was changed. HyperTonicity but not hyperosmolality is effective in activation of TonEBP as expected. Surprisingly, exposure to hypotonic medium leads to a dramatic downregulation of TonEBP both in abundance and nuclear distribution, indicating that under isotonic conditions, TonEBP is at a low-level activated state and can respond to both increase and decrease in Tonicity. Additional experiments suggest that cellular ionic strength is the signal that initiates regulation of TonEBP. The increase in abundance of TonEBP is mediated by an increase in mRNA abundance and a parallel increase in synthesis of TonEBP. The stability of TonEBP mRNA is not affected by hyperTonicity indicating that transcription plays a major role in the induction of TonEBP by hyperTonicity.
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nuclear redistribution of Tonicity responsive enhancer binding protein requires proteasome activity
American Journal of Physiology-cell Physiology, 2000Co-Authors: Djikolngar Maouyo, Joseph S Handler, Moo H KwonAbstract:Tonicity-responsive enhancer binding protein (TonEBP) is the transcription factor that regulates Tonicity-responsive expression of the genes for the sodium-myo-inositol cotransporter (SMIT) and the...
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kidney cell survival in high Tonicity
Comparative Biochemistry and Physiology Part A: Physiology, 1997Co-Authors: Joseph S Handler, Moo H KwonAbstract:Abstract The kidney medulla of mammals undergoes large changes in Tonicity in parallel with the Tonicity of the final urine that emerges from the kidney at the tip of the medulla. When the medulla is hypertonic, its cells accumulate the compatible osmolytes myo -inositol, betaine, taurine, sorbitol and glycerophosphorylcholine. The mechanisms by which the compatible osmolytes are accumulated have been explored extensively in kidney-derived cells in culture. Myo -inositol, betaine and taurine are accumulated by increased activity of specific sodium-coupled transporters, sorbitol by increased synthesis of aldose reductase that catalyses the synthesis of sorbitol from glucose. Glycerophosphorylcholine accumulates primarily because its degradation is reduced in cells in hypertonic medium. cDNAs for the cotransporters and for aldose reductase have been cloned and used to establish that hyperTonicity increases the transcription of the genes for the cotransporters for myo -inositol, betaine and for aldose reductase. The region 5′ to the promoter of the gene for the betaine cotransporter and for aldose reductase confer osmotic responsiveness to a heterologous promoter. The 12-bp sequence responsible for the transcriptional response to hyperTonicity has been identified in the 5′ region of the gene for the betaine cotransporter.
Maurice B Burg - One of the best experts on this subject based on the ideXlab platform.
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Tonicity regulated gene expression
Methods in Enzymology, 2007Co-Authors: Joan D Ferraris, Maurice B BurgAbstract:Abstract HyperTonicity activates several different transcription factors, including TonEBP/OREBP, that in turn increase transcription of numerous genes. HyperTonicity elevates TonEBP/OREBP transcriptional activity by moving it into the nucleus, where it binds to its cognate DNA element (ORE), and by increasing its transactivational activity. This chapter presents protocols for measuring the transcriptional activity of TonEBP/OREBP and determining its subcellular localization, its binding to OREs, and activity of its transactivation domain.
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camp independent role of pka in Tonicity induced transactivation of Tonicity responsive enhancer osmotic response element binding protein
Proceedings of the National Academy of Sciences of the United States of America, 2002Co-Authors: Joan D Ferraris, Prita Persaud, Chester K Williams, Ye Chen, Maurice B BurgAbstract:HyperTonicity-induced increase in activity of the transcription factor Tonicity-responsive enhancer/osmotic response element-binding protein (TonEBP/OREBP) protects renal cells by increasing transcription of genes, including those involved in increased accumulation of organic osmolytes. We previously showed that hyperTonicity increases transactivating activity of TonEBP/OREBP. Assay with a binary GAL4 transactivation system showed that the 984 C-terminal amino acids of TonEBP/OREBP (amino acids 548–1531) contain a Tonicity-dependent transactivation domain (TAD). Also, amino acids 548–1531 undergo Tonicity-dependent phosphorylation, and some inhibitors of protein kinases reduce the Tonicity-dependent transactivation. In the present studies we examined the role of protein kinase A (PKA). Results: (i) An inhibitor of PKA (H89) reduces Tonicity-dependent increases in transactivation, ORE/TonE reporter activity, and induction of aldose reductase and betaine transporter mRNAs. (ii) Overexpression of the catalytic subunit of PKA (PKAc) increases transactivation activity of amino acids 548–1531 and activity of an ORE/TonE reporter. The increases are much greater under isotonic than under hypertonic conditions. (iii) A dominant-negative PKAc reduces activity of an ORE/TonE reporter. (iv) PKAc activity increases with Tonicity but cAMP does not. (v) TonEBP/OREBP and PKAc coimmunoprecipitate. (vi) amino acids 872–1271, including N– and C-terminal polyglutamine stretches, demonstrate Tonicity-dependent transactivation, albeit less than amino acids 548–1531, and a similar role for PKA. Conclusions: (i) PKA plays an important role in TonEBP/OREBP activation of Tonicity-dependent gene expression; (ii) PKA activation of TonEBP/OREBP appears to be cAMP-independent; and (iii) amino acids 872–1271 are sufficient for Tonicity-dependent transactivation of TonEBP/OREBP.
Brian Curran - One of the best experts on this subject based on the ideXlab platform.
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the effect of Tonicity and hypertonic solutions on microvascular permeability
Journal of Surgical Research, 2002Co-Authors: Gregory P Victorino, Christopher R Newton, Brian CurranAbstract:Background. The effect of hypertonic saline (HS) on microvascular permeability is unclear. We hypothesized that varying degrees of Tonicity and HS solutions alter microvascular fluid flux across the endothelium. Methods. Hydraulic permeability (Lp) is a measure of water flow across the endothelial barrier. Lp was measured in cannulated rat mesenteric venules using the modified Landis micro-occlusion technique. The effect of Tonicity was tested by measuring Lp after successive perfusions with Ringers' solutions of varying sodium chloride (NaCl) concentrations (85, 135, 185, and 235 mM) (n = 6). Additional venules were perfused with control Ringers' ([NaCl] = 135 mM) and measures of Lp were obtained after subsequent perfusions with 7% NaCl followed by 7% NaCl with 6% dextran (n = 6). Results. Tonicity had a significant dose-dependent effect on Lp (P < 0.0001). Perfusion with 7% NaCl significantly increased Lp (P < 0.0001). The addition of 6% dextran to 7% NaCl significantly decreased Lp compared with perfusion with 7% NaCl alone (P = 0.002). Conclusions. We conclude that (1) Tonicity influences microvascular permeability, (2) HS increases microvascular permeability, and (3) the addition of dextran to HS greatly attenuates this response. These findings suggest an important role for Tonicity and a possible deleterious effect of HS in modulating microvascular permeability as well as the benefit of dextran with HS for maintaining intravascular volume.
Frank Thevenod - One of the best experts on this subject based on the ideXlab platform.
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Tonicity inversely modulates lipocalin 2 lcn2 24p3 ngal receptor slc22a17 and lcn2 expression via wnt β catenin signaling in renal inner medullary collecting duct cells implications for cell fate and bacterial infection
Cell Communication and Signaling, 2018Co-Authors: R Betten, Bettina Scharner, S Probst, B Edemir, Natascha A Wolff, Christian Langelueddecke, Frank ThevenodAbstract:We have previously evidenced apical expression of the 24p3/NGAL/lipocalin-2 receptor (Lcn2-R; SLC22A17) in inner medullary collecting duct (IMCD) cells, which are present in vivo in a hyperosmotic/-tonic environment that activates canonical Wnt/β-catenin signaling. The localization of Lcn2-R in the inner medulla is intriguing considering local bacterial infections trigger toll-like receptor-4 (TLR-4)-mediated secretion of the bacteriostatic Fe3+-free (apo-)Lcn2. To determine the effects of osmolarity/Tonicity changes, Wnt/β-catenin and TLR-4 activation on Lcn2-R and Lcn2 expression and cell viability in rat primary IMCD and mouse (m)IMCD3 cells. Normosmolarity/-Tonicity was 300 mosmol/l whereas hyperosmolarity/-Tonicity was induced by adding 100 mmol/l NaCl + 100 mmol/l urea (600 mosmol/l, 1-7 days). Lcn2-R and Lcn2 expression were determined by qPCR, immunoblotting, flow cytometry and immunofluorescence microscopy. β-catenin was silenced by RNAi. Cell viability/death was determined with MTT and LDH release assays. TLR-4 was activated by bacterial lipopolysaccharides (LPS). Hyperosmotic/-tonic media upregulated Lcn2-R by ~4-fold and decreased Lcn2 expression/secretion, along with Wnt/β-catenin activation, in IMCD cells. These effects of hyperosmotic/-tonic media on Lcn2-R/Lcn2 expression were reverted by normosmolarity/-Tonicity, β-catenin silencing and/or LPS. Exposure of cells with endogenous or stably overexpressing Lcn2-R to apo-Lcn2 or LPS decreased cell viability. Lcn2-R upregulation and Lcn2 downregulation via Wnt/β-catenin may promote adaptive osmotolerant survival of IMCD cells in response to hyperosmolarity/-Tonicity whereas Lcn2 upregulation and Lcn2-R downregulation via TLR-4 and/or normosmolarity/-Tonicity may protect IMCD cells against bacterial infections and prevent autocrine death induction by Lcn2.
