The TonE/TonEBP Pathway Mediates Tonicity-responsive Regulation of UT-A Urea Transporter Expression

Nakayama, Yushi; Peng, Tao; Sands, Jeff M.; Bagnasco, Serena M.

doi:10.1074/jbc.m004678200

Cited by 136 publications

(110 citation statements)

References 23 publications

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“…In this regard, up-regulation of Nup88 with urea may be explained by the fact that urea transporter A is a target gene for TonEBP under urea conditions, as shown previously by others (33,34). Localization of Nup88 protein in IMCD3 cells by con- focal fluorescence microscopy demonstrated its presence exclusively at the nuclear membrane, consistent with the protein's potential involvement in nuclear pore complexes (18).…”

Section: Discussionsupporting

confidence: 55%

Nucleoporin 88 (Nup88) Is Regulated by Hypertonic Stress in Kidney Cells to Retain the Transcription Factor Tonicity Enhancer-binding Protein (TonEBP) in the Nucleus

Andrés-Hernando

Lanaspa

Rivard

et al. 2008

Journal of Biological Chemistry

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Antibody microarray technology identified Nup88 (nucleoporin 88) as a highly up-regulated protein in response to osmotic stress in inner medullary collecting duct (IMCD3) cells. Changes in expression were verified by Western blot and quantitative PCR for protein and message expression. In mouse and human kidney, Nup88 expression was substantial in the papilla, whereas it was nearly absent in the cortex. Furthermore, the expression of Nup88 increased 410.4 ؎ 22% in the papilla of mice after 36 h of thirsting. Nup88 protein expression in IMCD3 cells was significantly up-regulated in the first 8 h following exposure to acute osmotic stress, indicating that Nup88 is an early response protein. To define the function of Nup88 in the osmotic stress response, the transcription factor associated with hypertonicity, tonicity enhancer-binding protein (TonEBP), was cloned upstream of the green fluorescent protein. Employing this construct, we demonstrate that silencing Nup88 in IMCD3 cells acutely stressed to hypertonic conditions reduces nuclear retention of TonEBP, resulting in a substantial blunting in transcription of important osmotic stress response target genes and reduced cell viability. Finally, we show that in IMCD3 cells, nuclear export of TonEBP under isotonic conditions involves CRM-1 but under hypertonic stress is CRM1-independent. Our data, therefore, suggest that Nup88 is up-regulated in response to hypertonic stress and acts to retain TonEBP in the nucleus, activating transcription of critical osmoprotective genes.The cells that inhabit the hypertonic environment of the inner medulla of the kidney possess a number of adaptative mechanisms that allow them to survive in this environment (1-5). The classical osmotic stress response involves the prompt transcription of several target genes by the tonicity enhancer-binding protein (TonEBP), 2 also known as NFAT5(6 -9). Under isotonic conditions (300 mosmol/kg H 2 O), TonEBP is mainly present in the cytosol with only minor localization in the nucleus. However, under hypertonic stress, TonEBP is translocated to the nucleus, where it enhances the transcription of genes that are important in the early osmotic stress response. These genes includes aldose reductase (AR) (10), the sodium-myoinositol transporter (10), the BGT1 (betaine/GABA transporter 1) (11), the taurine transporter (TauT) (12), and heat shock protein 70 (Hsp70) (13) among others. Expression of these target genes results in the accumulation of a number of compatible organic osmolytes (mainly sorbitol, myoinositol, betaine, and taurine) that allow the cell to compensate the extracellular osmotic gradient and, hence, adapt to hypertonic stress (see Refs. 3 and 6 -9 for excellent reviews). One of the main mechanisms involved in the regulation of TonEBP activity under hypertonic stress is nucleocytoplasmic trafficking (7, 9, 14, 15). Our laboratory has employed several proteomic approaches, including two-dimensional difference gel electrophoresis (16) and antibody microarray (17) technologies to evaluate ...

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Section: Discussionsupporting

confidence: 55%

Nucleoporin 88 (Nup88) Is Regulated by Hypertonic Stress in Kidney Cells to Retain the Transcription Factor Tonicity Enhancer-binding Protein (TonEBP) in the Nucleus

Andrés-Hernando

Lanaspa

Rivard

et al. 2008

Journal of Biological Chemistry

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“…It has been shown that UT-A2 gene expression is under the control of a promoter capable of responding to changes in tonicity [34,35]. The UT-A2 mRNA was, however, not changed in diabetic rats.…”

Section: Discussionmentioning

confidence: 98%

Aquaporin-2 and urea transporter-A1 are up-regulated in rats with Type I diabetes mellitus

et al. 2001

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In diabetes mellitus, water turnover in the body is enhanced because of the glucose-induced osmotic diuresis and it is usually assumed that the concentrating capacity of the kidney is partially impaired. On the other hand, plasma vasopressin concentration is known to be increased by several fold in patients with Type I (insulin-dependent) diabetes mellitus or Type II (non-insulin-dependent) diabetes mellitus as well as in animal models of experimental or genetic diabetes mellitus [1±6]. This high vasopressin concentration is accompanied by a desensitization of V1 a receptors in liver, kidney and platelets [7,8]. In contrast, renal V2 receptors, responsible for the antidiuretic action of the hormone, are not down-regulated [8].Actually, higher vasopressin in diabetes mellitus probably represents an appropriate adaptation by limiting to some extent the amount of water required Abstract Aims/hypothesis. Although the urine flow rate is considerably higher in diabetes mellitus, water reabsorption is greatly increased to concentrate an increased amount of solutes. Our study evaluated the expression of aquaporins and urea transporters, which are essential to the urinary concentration process. Methods. Northern blot and immunoblot were used to quantify mRNA and proteins for aquaporin-2 (AQP2) as well as urea transporters UT-A1, UT-A2 and UT-B1, in subzones of the renal medulla of rats with streptozotocin-induced diabetes. Results. In these rats, glycaemia, urine flow rate and water reabsorption were respectively fourfold, ninefold and fourfold those of control rats. The AQP2 protein isoforms were significantly up-regulated in outer and inner medulla. In the base and tip of inner medulla, UT-A1 mRNA was significantly up-regulated (three-and 1.3-fold, respectively) as well as the 117 kD protein (ten-and threefold, respectively) whereas the 97 kD protein was not changed or decreased twofold, respectively. This suggests that, in diabetes, the inner medullary collecting duct is endowed with more UT-A1, especially in its initial part. In the case of mRNA and proteins of UT-A2, located in thin descending limbs in the inner stripe of outer medulla, they were respectively not changed and down-regulated in diabetic rats. Conclusion/interpretation. This study shows that in diabetes, the increased expression of AQP2 and UT-A1 in medullary collecting duct is consistent with an improved concentrating activity. In addition, the underexpression of UT-A2 and the overexpression of UT-A1 in the initial medullary collecting duct are reminiscent of the changes seen after experimental reduction of urine concentration or low protein feeding. [Diabetologia (2001) 44: 637±645]

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“…TonEBP participates in compatible osmolyte accumulation by upregulating AR (40,41), BGT1 (42,43), and SMIT (44) mRNA expression. In addition, TonEBP regulates expression of other genes such as UT-A and HSP70 -2 (8,45). Enhanced AR, BGT1, and SMIT expression after hypertonic stimulation in mpkCCD cl4 cells is indicative of TonEBP activity.…”

Section: Discussionmentioning

confidence: 99%

Dual Effects of Hypertonicity on Aquaporin-2 Expression in Cultured Renal Collecting Duct Principal Cells

Hasler¹,

Vinciguerra²,

Vandewalle³

et al. 2005

Journal of the American Society of Nephrology

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The driving force for renal water reabsorption is provided by the osmolarity gradient between the interstitium and the tubular lumen, which is subject to rapid physiologic variations as a consequence of water intake fluctuations. The effect of increased extracellular tonicity/osmolarity on vasopressin-inducible aquaporin-2 (AQP2) expression in immortalized mouse collecting duct principal cells (mpkCCD cl4 ) is investigated in this report. Increasing the osmolarity of the medium either by the addition of NaCl, sucrose, or urea first decreased AQP2 expression after 3 h. AQP2 expression then increased in cells exposed to NaClor sucrose-supplemented hypertonic medium after longer periods of time (24 h), while urea-supplemented hyperosmotic medium had no effect. Altered AQP2 expression induced by both short-term (3 h) and long-term ( A quaporin (AQP) water channels facilitate osmoticallydriven water movement across renal epithelial cells by forming aqueous pores across the plasma membrane. Currently, 10 members of the AQP family have been identified in mammals and at least 7 of these are expressed in the kidney (1,2). In the collecting duct (CD), the site of final adjustment of water excretion, water permeability is chiefly controlled by the antidiuretic hormone [8-arginine]vasopressin (AVP), which binds to vasopressin V 2 receptors of CD principal cells, leading to G s ␣/adenylyl cyclase activation, increased intracellular cAMP concentration, and cAMP-protein kinase (PKA) activation (2). An acute increase in plasma AVP concentration induces rapid AQP2 translocation from intracellular storage vesicles to the apical membrane (3) responsible for enhanced apical water permeability. Water exits the cells via basolateral AQP3 and AQP4 (4,5). Diminishing levels of circulating AVP leads to endocytotic retrieval of apical AQP2 and to reduced water permeability (3). Conversely, sustained increases in circulating AVP increase AQP2 and AQP3 abundance (6) and consequently maximal CD water permeability.Water excretion is dependent on the corticopapillary osmotic gradient which arises from interstitial accumulation of both urea and NaCl. This gradient decreases during water diuresis and increases under conditions of antidiuresis (2). Consequently, renal medullary cells are subject to fluctuations of interstitial osmolarity. Renal epithelial cells protect themselves from the effects of hypertonicity-induced cell shrinkage and osmotic stress chiefly by activating specific, immediate, early-regulated genes (7), heat shock genes (7,8), and genes that enhance accumulation of small organic solutes, known as compatible osmolytes, which in turn lower cellular ionic strength toward isotonic levels (9). Because water restriction increases AQP2 abundance in rat kidney despite chronic administration of V 2 -receptor antagonists (10), interstitial hyperosmolarity may regulate AQP2 expression as well. The aim of this study was to investigate the influence of increased extracellular tonicity/osmolarity on AQP2 abundance in the immortalized mouse...

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The TonE/TonEBP Pathway Mediates Tonicity-responsive Regulation of UT-A Urea Transporter Expression

Cited by 136 publications

References 23 publications

Nucleoporin 88 (Nup88) Is Regulated by Hypertonic Stress in Kidney Cells to Retain the Transcription Factor Tonicity Enhancer-binding Protein (TonEBP) in the Nucleus

Nucleoporin 88 (Nup88) Is Regulated by Hypertonic Stress in Kidney Cells to Retain the Transcription Factor Tonicity Enhancer-binding Protein (TonEBP) in the Nucleus

Aquaporin-2 and urea transporter-A1 are up-regulated in rats with Type I diabetes mellitus

Dual Effects of Hypertonicity on Aquaporin-2 Expression in Cultured Renal Collecting Duct Principal Cells

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