Medium tonicity regulates expression of the Na(+)- and Cl(-)-dependent betaine transporter in Madin-Darby canine kidney cells by increasing transcription of the transporter gene.

Uchida, Shinichi; Yamauchi, Atsushi; Preston, A.; Kwon, H. Moo; Handler, Jerome S.

doi:10.1172/jci116367

Cited by 119 publications

(69 citation statements)

References 21 publications

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“…In AT cells, raising the osmolality from 300 to 500 mosmol͞kg by adding NaCl increases TonEBP͞OREBP transcriptional activity far less than in HEK293 cells, but wortmannin at 1 or 20 M still significantly inhibits the response, indicating the involvement of kinases in addition to ATM. Activation of TonEBP͞OREBP by hypertonicity increases transcription and mRNA abundance of BGT1 (22). Accordingly, raising osmolality from 300 to 500 mosmol͞kg by adding NaCl for 16 h greatly increases BGT1 mRNA abundance in HEK293 cells (Fig.…”

Section: Resultsmentioning

confidence: 90%

ATM, a DNA damage-inducible kinase, contributes to activation by high NaCl of the transcription factor TonEBP/OREBP

Irarrázabal

Liu

Burg

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

106

174

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High NaCl activates the transcription factor tonicity-responsive enhancer/osmotic response element-binding protein (TonEBP/OREBP), resulting in increased transcription of several protective genes, including the glycine betaine/γ-aminobutyric acid transporter (BGT1). High NaCl damages DNA, and DNA damage activates ataxia telangiectasia mutated (ATM) kinase through autophosphorylation on Ser-1981. TonEBP/OREBP contains ATM consensus phosphorylation sites at Ser-1197, Ser-1247, and Ser-1367. The present studies test whether ATM is involved in activation of TonEBP/OREBP by high NaCl. We find that raising osmolality from 300 to 500 mosmol/kg by adding NaCl activates ATM, as indicated by phosphorylation at Ser-1981. High urea and radiation also activate ATM, but they do not increase TonEBP/OREBP transcriptional activity like high NaCl does. Wortmannin, which inhibits ATM, reduces NaCl-induced TonEBP/OREBP transcriptional activation and BGT1 mRNA increase. Overexpression of wild-type TonEBP/OREBP increases ORE/TonE reporter activity much more than does overexpression of TonEBP/OREBP S1197A, S1247A, or S1367A. In AT cells (which express nonfunctional ATM), TonEBP/OREBP transcriptional and transactivating activity are further increased by expression of wild-type ATM but not of S1981A ATM. TonEBP/OREBP reciprocally coimmunoprecipitates with ATM kinase, demonstrating physical association. Additionally, antibody to ATM kinase supershifts TonEBP/OREBP bound to its cognate ORE/TonE DNA element. In AT cells, wortmannin further decreases high NaCl-induced increase in transcriptional activity, consistent with participation of signaling kinase(s) in addition to ATM. In conclusion, signaling via ATM is necessary for full activation of TonEBP/OREBP by high NaCl, but it is not sufficient

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Section: Resultsmentioning

confidence: 90%

ATM, a DNA damage-inducible kinase, contributes to activation by high NaCl of the transcription factor TonEBP/OREBP

Irarrázabal

Liu

Burg

et al. 2004

Proc. Natl. Acad. Sci. U.S.A.

106

174

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“…Mutation of this site led to a reduction in promoter stimulation by the osmotic stimulus. This varies somewhat from the more typical osmotic induction of promoter activity involving a specific regulatory element termed the osmotic regulatory element (TGGAAAATTAC 18 ) found in the 5Ј flanking sequence of a number of osmotically sensitive genes, including those encoding the sodium/myo-inositol co-transporter, 4 sodium/chloride/betaine co-transporter, 5 and aldose reductase. 6 The use of an Sp1 site to mediate the osmotic induction implies that basal transcription factors can be recruited into a regulatory mode in response to changes in extracellular tonicity.…”

Section: Discussionmentioning

confidence: 96%

Sgk1 Mediates Osmotic Induction of NPR-A Gene in Rat Inner Medullary Collecting Duct Cells

Chen¹,

McCormick²,

Prabaker³

et al. 2004

Hypertension

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Abstract-We have shown previously that increased extracellular osmolality stimulates expression and promoter activity of the type A natriuretic peptide receptor (NPR-A) gene in rat inner medullary collecting duct (IMCD) cells through a mechanism that involves activation of p38 mitogen-activated protein kinase (MAPK). The serum and glucocorticoid inducible kinase (Sgk) is thought to participate in the regulation of sodium handling in distal tubular segments. We sought to determine whether this kinase might be involved in the osmotic stimulation of NPR-A gene promoter activity. Exposure of cultured IMCD cells to an additional 75 mmol/L NaCl in culture media (final osmolality 475 mosm/kg) resulted in an Ϸ4-fold increase in Sgk1 protein levels after 7 hours. The Sgk1 induction was almost completely inhibited by the p38 MAPK inhibitor SB203580, indicating that NaCl activates Sgk1 through the p38 MAPK pathway. Transient transfection of a mouse Sgk1 expression vector along with a Ϫ1590 NPR-A luciferase reporter resulted in an Ϸ3-fold increment in reporter activity, which was significantly reduced by cotransfection with a kinase-dead Sgk1 mutant. The NaCl-dependent induction was partially blocked (Ϸ40% inhibition) by cotransfection of the kinase-dead Sgk1 mutant. Neither Sgk1 nor the kinase-dead mutant had any effect on endothelial nitric oxide synthase (eNOS) promoter activity, and the Sgk1 mutant and 8-bromo-cyclic guanosine monophosphate were, to some degree, additive in reducing osmotically stimulated NPR-A promoter activity. Collectively, these data imply that Sgk1 operates over an eNOS-independent, p38 MAPK-dependent pathway in mediating osmotic induction of the NPR-A gene promoter. Key Words: glucocorticoids Ⅲ kinase Ⅲ receptors Ⅲ atrial natriuretic factor Ⅲ gene regulation Ⅲ signal transduction T he inner medullary collecting duct is the terminal nephron segment responsible for the final regulation of urinary sodium content. It is the target of several hormonal systems that promote either sodium retention or sodium excretion. 1 The natriuretic peptides are a family of peptide hormones that promote a natriuretic diuresis in the kidney through a combination of vasoregulatory properties and direct effects on sodium transport in the collecting duct epithelial cell. 2 There are 3 types of natriuretic peptides and 3 classes of receptors that signal their activities. Atrial natriuretic peptide and brain natriuretic peptide are produced primarily in the heart (atria and ventricles, respectively), whereas C type natriuretic peptide is produced in a variety of extracardiac tissues including the vascular endothelium. Atrial natriuretic peptide and brain natriuretic peptide interact primarily with the type A natriuretic peptide receptor (NPR-A), whereas C type natriuretic peptide binds to and activates the type B receptor (NPR-B). 2 Each of these receptors is a particulate guanylyl cyclase. Occupancy of the receptor by ligand increases cyclase activity and, thereby, increases cyclic GMP levels in the target cell. In the kid...

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“…Despite an overall decrease in total DNA synthesis, RNA transcription, and protein synthesis (17), a limited number of genes are up-regulated in response to hypertonic stress (18,19), although the number may be as high as 3% of the genome in Saccharomyces (20). Transcriptional activation of genes whose products participate in transport or synthesis of compatible osmolytes (e.g., betaine, sodium myoinositol) in response to hyperosmolar stress is well established (21,22). Signaling through mitogen-activated protein kinases has been implicated in hypertonic induction of the betaine transporter and sodium myo-inositol cotransporter (23,24), AQP5 (25), and AQP1 (L.K., unpublished observations).…”

Section: Discussionmentioning

confidence: 99%

Altered ubiquitination and stability of aquaporin-1 in hypertonic stress

Leitch

Agre

King

2001

Proc. Natl. Acad. Sci. U.S.A.

127

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Aquaporin-1 (AQP1) water channel protein expression is increased by hypertonic stress. The contribution of changes in protein stability to hypertonic induction of AQP1 have not been described. Incubation of BALB͞c fibroblasts spontaneously expressing AQP1 with proteasome inhibitors increased AQP1 expression, suggesting basal proteasome-dependent degradation of the protein. Degradation by the proteasome is thought to be triggered by polyubiquitination of a target protein. To determine whether AQP1 is ubiquitinated, immunoprecipitation with anti-AQP1 antibodies was performed, and the resultant samples were probed by protein immunoblot for the presence of ubiquitin. Immunoblots demonstrated ubiquitination of AQP1 under control conditions that increased after treatment with proteasome inhibitors (MG132, lactacystin). Exposure of cells to hypertonic medium for as little as 4 h decreased ubiquitination of AQP1, an effect that persisted through 24 h in hypertonic medium. Using metabolic labeling with [ 35 S]methionine, the half-life of AQP1 protein under isotonic conditions was found to be <4 h. AQP1 protein half-life was markedly increased by exposure of cells to hypertonic medium. These observations provide evidence that aquaporins are a target for ubiquitination and proteasome-dependent degradation. Additionally, these studies demonstrate that reduced protein ubiquitination and increased protein stability lead to increased levels of AQP1 expression during hypertonic stress.A quaporin-1 (AQP1) is a water channel protein expressed in many tissues, whose regulation is known to be complex (1). Age-and tissue-specific patterns of AQP1 expression have been shown for kidney, lung, brain, and eye (2, 3). Corticosteroids induce AQP1 in rat lung in vivo (3) and an erythroleukemia cell line in vitro (4); the AQP1 proximal promoter contains classical glucorticoid response elements to which activity has been localized. AQP1 expression is induced by hypertonic stress in kidney cells lines (5, 6), as well as in BALB͞c fibroblasts in culture and in rat in vivo (L.K., unpublished observations). A potential role for posttranslational events in the regulation of AQP1 expression has not been described.It is increasingly apparent that posttranslational events play an active role in determining the level of protein expression in a cell. Two major protein degradative pathways are known to operate in mammalian cells, the 26S proteasome (7), and cysteine proteases, including cytoplasmic calcium-dependent calpains (8) and lysosomal acidic cathepsins (9). The 76-aa protein ubiquitin plays a key role in proteasome-mediated protein degradation, because polyubiquitination of a target protein is a necessary signal for processing by the proteasome (7). A limited number of membrane transport proteins have been demonstrated to be ubiquitinated (10). Ubiquitination has not been shown for any member of the aquaporin family of proteins.The studies reported here examine the role of ubiquitination and protein degradation in hypertonic induction of AQP1 e...

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Medium tonicity regulates expression of the Na(+)- and Cl(-)-dependent betaine transporter in Madin-Darby canine kidney cells by increasing transcription of the transporter gene.

Cited by 119 publications

References 21 publications

ATM, a DNA damage-inducible kinase, contributes to activation by high NaCl of the transcription factor TonEBP/OREBP

ATM, a DNA damage-inducible kinase, contributes to activation by high NaCl of the transcription factor TonEBP/OREBP

Sgk1 Mediates Osmotic Induction of NPR-A Gene in Rat Inner Medullary Collecting Duct Cells

Altered ubiquitination and stability of aquaporin-1 in hypertonic stress

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