Dehydration activates an NF-κB–driven, COX2-dependent survival mechanism in renal medullary interstitial cells

Hao, Chuan‐Ming; Yull, Fiona E.; Blackwell, Timothy S.; Kömhoff, Martin; Davis, Linda S.; Breyer, Matthew D.

doi:10.1172/jci9956

Cited by 137 publications

(183 citation statements)

References 58 publications

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“…It has been reported that dehydration upregulates the expression of tonicity-sensitive genes, such as an ion channel (46), a solute cotransporter (47), a metabolic enzyme (48), and heat shock proteins (26,49) in the kidney in vivo. In vivo dehydration also induces the nuclear distribution of TonEBP/OREBP/NFAT5 in thick ascending limbs and the S3 segment (pars recta) of proximal tubules in the rat kidney (50).…”

Section: Probementioning

confidence: 99%

Hypertonicity-Induced Expression of Monocyte Chemoattractant Protein-1 through a Novel Cis-Acting Element and MAPK Signaling Pathways

Kojima

Taniguchi

Tsuzuki

et al. 2010

The Journal of Immunology

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MCP1 is upregulated by various stimuli, including LPS, high glucose, and hyperosmolality. However, the molecular mechanisms of transcriptional regulation of the MCP1 gene under hyperosmolar conditions are poorly understood. Treatment of NRK52E cells with NaCl or mannitol resulted in significant elevation of MCP1 mRNA and protein in a time- and dose-dependent manner. Treatment with a p38MAPK inhibitor (SB203580), an ERK inhibitor (PD98059), or an MEK inhibitor (U0126), suppressed the increase in MCP1 expression caused by hypertonic NaCl, whereas a JNK inhibitor (SP600125) and an AP1 inhibitor (curcumin) failed to attenuate MCP1 mRNA expression by NaCl. In the 5′-flanking region of the MCP1 gene, there is a sequence motif similar to the consensus TonE/ORE as well as the consensus C/E binding protein (BP), NF-κB, and AP1/Sp1 sites. Luciferase activity in cells transfected with reporter constructs containing a putative TonE/ORE element (MCP1-TonE/ORE) enhanced reporter gene expression under hypertonic stress. Results of electrophoretic gel mobility shift assay showed a slow migration of the MCP1-TonE/ORE probe, representing the binding of TonEBP/OREBP/NFAT5 to this enhancer element. These results indicate that the 5′-flanking region of MCP1 contains a hypertonicity-sensitive cis-acting element, MCP1-TonE/ORE, as a novel element in the MCP1 gene. Furthermore, p38MAPK and MEK–ERK pathways appear to be, at least in part, involved in hypertonic stress-mediated regulation of MCP1 expression through the MCP1-TonE/ORE.

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Section: Probementioning

confidence: 99%

Hypertonicity-Induced Expression of Monocyte Chemoattractant Protein-1 through a Novel Cis-Acting Element and MAPK Signaling Pathways

Kojima

Taniguchi

Tsuzuki

et al. 2010

The Journal of Immunology

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“…Because the HIV-LTR contains two NF-B enhancer elements that bind a broad range of homodimeric and heterodimeric NF-B complexes (Kretzschmar et al, 1992;Liu et al, 1992;Doerre et al, 1993), HLL transgenic animals have been used as a model to quantify both constitutive and induced NF-B activity in vivo in several organ systems, including the mammary gland Brantley et al, 2000;Hao et al, 2000). Mice heterozygous for the targeted ib␣ allele and hemizygous for the transgene were intercrossed to generate ib␣ Ϫ/Ϫ , ib␣ ϩ/Ϫ , or ib␣ ϩ/ϩ offspring that also harbored the HLL transgene.…”

Section: Ib␣-deficient Mammary Epithelium Displays Increased Ductal Bmentioning

confidence: 99%

Nuclear Factor-κB (NF-κB) Regulates Proliferation and Branching in Mouse Mammary Epithelium

Brantley

Chen

Muraoka³

et al. 2001

MBoC

131

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The nuclear factor-B (NF-B) family of transcription factors has been shown to regulate proliferation in several cell types. Although recent studies have demonstrated aberrant expression or activity of NF-B in human breast cancer cell lines and tumors, little is known regarding the precise role of NF-B in normal proliferation and development of the mammary epithelium. We investigated the function of NF-B during murine early postnatal mammary gland development by observing the consequences of increased NF-B activity in mouse mammary epithelium lacking the gene encoding IB␣, a major inhibitor of NF-B. Mammary tissue containing epithelium from inhibitor B␣ (IB␣)-deficient female donors was transplanted into the gland-free mammary stroma of wild-type mice, resulting in an increase in lateral ductal branching and pervasive intraductal hyperplasia. A two-to threefold increase in epithelial cell number was observed in IB␣-deficient epithelium compared with controls. Epithelial cell proliferation was strikingly increased in IB␣-deficient epithelium, and no alteration in apoptosis was detected. The extracellular matrix adjacent to IB␣-deficient epithelium was reduced. Consistent with in vivo data, a fourfold increase in epithelial branching was also observed in purified IB␣-deficient primary epithelial cells in three-dimensional culture. These data demonstrate that NF-B positively regulates mammary epithelial proliferation, branching, and functions in maintenance of normal epithelial architecture during early postnatal development. INTRODUCTIONThe mammary gland is an organ designed to deliver nourishment and passive immunity to infant mammals. It consists of an epithelium that synthesizes and secretes lipid and milk proteins, as well as a fatty stroma that provides support and local growth regulatory cues to the epithelium (reviewed by Medina, 1996). Although the mammary gland rudiment is established during embryogenesis, the majority of mammary gland development occurs postnatally. During puberty, the epithelium proliferates and branches in response to hormonal signals, eventually extending throughout the entire stroma. More extensive growth and differentiation of the epithelium occurs during each round of pregnancy. The distal tips of each epithelial branch proliferate and differentiate into lobuloalveoli, which synthesize and secrete milk during lactation. Upon cessation of nursing, the majority of the epithelium undergoes apoptosis in a process called involution (reviewed by Furth, 1999). After involution, the epithelium remains relatively quiescent until the next pregnancy, when the morphogenetic cycle is repeated.The nuclear factor-B (NF-B) family of transcription factors regulates growth, differentiation, and apoptosis in several tissues, including lymphocytes, embryonic limb, lung and liver, skin, and bone (Beg et al., 1995;Klement et al., 1996;Boothby et al., 1997;Franzoso et al., 1997;Bushdid et al., 1998;Kanegae et al., 1998;Seitz et al., 1998;Bendall et al., 1999;Hu et al., 1999; Li et al., 1999a,b,c;Takeda et...

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“…Similarly, hypertonicity activates NF-B in renal medullary interstitial cells, and water deprivation increases renal NF-B-driven reporter gene expression in transgenic mice (38). In addition, GATA may play a role in tonicity-regulated AQP2 transcription, because hypertonic stress induces transcription of GATA-2 in placental trophoblast stem cells (39).…”

Section: Discussion Mpkccd Cells Are a Proper Model To Study Tonicitymentioning

confidence: 99%

Hypotonicity-induced Reduction of Aquaporin-2 Transcription in mpkCCD Cells Is Independent of the Tonicity Responsive Element, Vasopressin, and cAMP

Kortenoeven¹,

Brand²,

Wetzels

et al. 2011

Journal of Biological Chemistry

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The syndrome of inappropriate antidiuretic hormone secretion is characterized by excessive water uptake and hyponatremia. The extent of hyponatremia, however, is less than anticipated, which is ascribed to a defense mechanism, the vasopressin-escape, and is suggested to involve a tonicity-determined down-regulation of the water channel aquaporin-2 (AQP2). The underlying mechanism, however, is poorly understood. To study this, we used the mouse cortical collecting duct (mpkCCD) cell line. MpkCCD cells, transfected with an AQP2-promoter luciferase construct showed a reduced and increased AQP2 abundance and transcription following culture in hypotonic and hypertonic medium, respectively. This depended on tonicity rather than osmolality and occurred independently of the vasopressin analog dDAVP, cAMP levels, or protein kinase A activity. Although prostaglandins and nitric oxide reduced AQP2 abundance, inhibition of their synthesis did not influence tonicity-induced AQP2 transcription. Also, cells in which the cAMP or tonicity-responsive element (CRE/TonE) in the AQP2-promoter were mutated showed a similar response to hypotonicity. Instead, the tonicity-responsive elements were pin-pointed to nucleotides ؊283 to ؊252 and ؊157 to ؊126 bp. In conclusion, our data indicate that hypotonicity reduces AQP2 abundance and transcription, which occurs independently of vasopressin, cAMP, and the known TonE and CRE in the AQP2-promoter. Increased prostaglandin and nitric oxide, as found in vivo, may contribute to reduced AQP2 in vasopressin-escape, but do not mediate the effect of hypotonicity on AQP2 transcription. Our data suggest that two novel segments (؊283 to ؊252 and ؊157 to ؊126 bp) in the AQP2-promoter mediate the hypotonicity-induced AQP2 downregulation during vasopressin-escape.Renal water reabsorption is regulated by the hormone arginine vasopressin (AVP).2 AVP binding to its V2 receptor in renal principal cells induces a cAMP cascade leading to increased translocation of the water channel aquaporin-2 (AQP2) to the apical membrane, resulting in water reabsorption from the pro-urine (1). In addition to this short-term effect, cAMP increases AQP2 transcription through phosphorylation of the transcription factor CREB (cAMP responsive element-binding protein), which then binds to a cAMP responsive element (CRE) at Ϫ210 in the AQP2 promoter (2, 3). The increase in transcription is a more long-term effect, requiring hours to take effect. AVP synthesis and release are regulated by alterations in plasma osmolality as well as non-osmotic, baroreceptor-mediated pathways (4). Osmolality not only affects plasma AVP, but also appears to have direct effects on urine concentrating ability and AQP2 expression. In the syndrome of inappropriate antidiuretic hormone secretion (SIADH), for example, levels of AVP are inappropriately high relative to plasma osmolality, resulting in free-water retention and hypotonicity. Under these circumstances, however, the free-water excretion is considerably higher than would be expected from the vaso...

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Dehydration activates an NF-κB–driven, COX2-dependent survival mechanism in renal medullary interstitial cells

Cited by 137 publications

References 58 publications

Hypertonicity-Induced Expression of Monocyte Chemoattractant Protein-1 through a Novel Cis-Acting Element and MAPK Signaling Pathways

Hypertonicity-Induced Expression of Monocyte Chemoattractant Protein-1 through a Novel Cis-Acting Element and MAPK Signaling Pathways

Nuclear Factor-κB (NF-κB) Regulates Proliferation and Branching in Mouse Mammary Epithelium

Hypotonicity-induced Reduction of Aquaporin-2 Transcription in mpkCCD Cells Is Independent of the Tonicity Responsive Element, Vasopressin, and cAMP

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