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  • 1
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    1α,25-Dihydroxyvitamin D 3 upregulates FGF23 gene expression in bone: the final link in a renal-gastrointestinal-skeletal axis that controls phosphate transport
    American Physiological Society ; 2005
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 289, No. 6 ( 2005-12), p. G1036-G1042
    Details
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 289, No. 6 ( 2005-12), p. G1036-G1042
    Abstract: Fibroblast growth factor (FGF)23 is a phosphaturic hormone that decreases circulating 1α,25-dihydroxyvitamin D 3 [1,25(OH) 2 D 3 ] and elicits hypophosphatemia, both of which contribute to rickets/osteomalacia. It has been shown recently that serum FGF23 increases after treatment with renal 1,25(OH) 2 D 3 hormone, suggesting that 1,25(OH) 2 D 3 negatively feedback controls its levels by inducing FGF23. To establish the tissue of origin and the molecular mechanism by which 1,25(OH) 2 D 3 increases circulating FGF23, we administered 1,25(OH) 2 D 3 to C57BL/6 mice. Within 24 h, these mice displayed a dramatic elevation in serum immunoreactive FGF23, and the expression of FGF23 mRNA in bone was significantly upregulated by 1,25(OH) 2 D 3 , but there was no effect in several other tissues. Furthermore, we treated rat UMR-106 osteoblast-like cells with 1,25(OH) 2 D 3 , and real-time PCR analysis revealed a dose- and time-dependent stimulation of FGF23 mRNA concentrations. The maximum increase in FGF23 mRNA was 1,024-fold at 10 −7 M 1,25(OH) 2 D 3 after 24-h treatment, but statistically significant differences were observed as early as 4 h after 1,25(OH) 2 D 3 treatment. In addition, using cotreatment with actinomycin D or cycloheximide, we observed that 1,25(OH) 2 D 3 regulation of FGF23 gene expression occurs at the transcriptional level, likely via the nuclear vitamin D receptor, and is dependent on synthesis of an intermediary transfactor. These results indicate that bone is a major site of FGF23 expression and source of circulating FGF23 after 1,25(OH) 2 D 3 administration or physiological upregulation. Our data also establish FGF23 induction by 1,25(OH) 2 D 3 in osteoblasts as a feedback loop between these two hormones that completes a kidney-intestine-bone axis that mediates phosphate homeostasis.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    URL: Article
    DOI: 10.1152/ajpgi.00243.2005
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2005
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  • 2
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    Regulation of the rat NHE3 gene promoter by sodium butyrate
    American Physiological Society ; 2001
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 281, No. 4 ( 2001-10-01), p. G947-G956
    Details
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 281, No. 4 ( 2001-10-01), p. G947-G956
    Abstract: Short-chain fatty acids, and especially butyrate (NaB), stimulate sodium and water absorption by inducing colonic Na + /H + exchange (NHE). NaB induces NHE3 activity and protein and mRNA expression both in vivo and in vitro. NaB, as a histone deacetylase (HDAC) inhibitor, regulates gene transcription. We therefore studied whether NaB regulates transcription of the rat NHE3 promoter in transiently transfected Caco-2 cells. NaB (5 mM) strongly stimulated reporter gene activity, and this stimulation was prevented with actinomycin D, indicating transcriptional activation. NaB effects on the NHE3 promoter depended on the activity of Ser/Thr kinases, in particular, protein kinase A (PKA). However, PKA stimulation alone did not have an effect on promoter activity, and it did not act synergistically with NaB. Another HDAC inhibitor, Trichostatin A (TSA), stimulated NHE3 promoter in a Ser/Thr kinase-independent fashion. The putative NaB-responsive elements were localized within −320/−34 bp of the NHE3 promoter. These findings suggest that PKA mediates NaB effects on NHE3 gene transcription and that the mechanism of NaB action is different from that of TSA.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    URL: Article
    DOI: 10.1152/ajpgi.2001.281.4.G947
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2001
    detail.hit.zdb_id: 1477329-6
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  • 3
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    Glucocorticoid regulation and glycosylation of mouse intestinal type IIb Na-P i cotransporter during ontogeny
    American Physiological Society ; 2002
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 283, No. 2 ( 2002-08-01), p. G426-G434
    Details
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 283, No. 2 ( 2002-08-01), p. G426-G434
    Abstract: We sought to characterize expression of an apically expressed intestinal Na-P i cotransporter (Na-P i -IIb) during mouse ontogeny and to assess the effects of methylprednisolone (MP) treatment. In control mice, Na-P i uptake by intestinal brush-border membrane vesicles was highest at 14 days of age, lower at 21 days, and further reduced at 8 wk and 8–9 mo of age. Na-P i -IIb mRNA and immunoreactive protein levels in 14-day-old animals were markedly higher than in older groups. MP treatment significantly decreased Na-P i uptake and Na-P i -IIb mRNA and protein expression in 14-day-old mice. Additionally, the size of the protein was smaller in 14-day-old mice. Deglycosylation of protein from 14-day-old and 8-wk-old animals with peptide N-glycosidase reduced the molecular weight to the predicted size. We conclude that intestinal Na-P i uptake and Na-P i -IIb expression are highest at 14 days and decrease with age. Furthermore, MP treatment reduced intestinal Na-P i uptake approximately threefold in 14-day-old mice and this reduction correlates with reduced Na-P i -IIb mRNA and protein expression. We also demonstrate that Na-P i -IIb is an N-linked glycoprotein and that glycosylation is age dependent.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    URL: Article
    DOI: 10.1152/ajpgi.00319.2001
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2002
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  • 4
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    Epidermal growth factor regulation of rat NHE2 gene expression
    American Physiological Society ; 2001
    In:  American Journal of Physiology-Cell Physiology Vol. 281, No. 2 ( 2001-08-01), p. C504-C513
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 281, No. 2 ( 2001-08-01), p. C504-C513
    Abstract: Epidermal growth factor (EGF) is involved in acute regulation of Na + /H + exchangers (NHEs), but the effect of chronic EGF administration on NHE gene expression is unknown. The present studies showed that EGF treatment increased NHE2-mediated intestinal brush-border membrane vesicle Na + absorption and NHE2 mRNA abundance by nearly twofold in 19-day-old rats. However, no changes were observed in renal NHE2 mRNA or intestinal and renal NHE3 mRNA abundance. To understand the mechanism of this regulation, we developed the rat intestinal epithelial (RIE) cell as an in vitro model to study the effect of EGF on NHE2 gene expression. EGF increased functional NHE2 activity and mRNA abundance in cultured RIE cells, and this stimulation could be blocked by actinomycin D (a transcriptional inhibitor). Additionally, NHE2 promoter reporter gene assays in transiently transfected RIE cells showed an almost twofold increase in promoter activity after EGF treatment. We conclude that rat NHE2 activity can be stimulated by chronic EGF treatment and that this response is at least partially mediated by gene transcription.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.2001.281.2.C504
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2001
    detail.hit.zdb_id: 1477334-X
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  • 5
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    Advances in the understanding of mineral and bone metabolism in inflammatory bowel diseases
    American Physiological Society ; 2011
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 300, No. 2 ( 2011-02), p. G191-G201
    Details
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 300, No. 2 ( 2011-02), p. G191-G201
    Abstract: Chronic inflammatory disorders such as inflammatory bowel diseases (IBDs) affect bone metabolism and are frequently associated with the presence of osteopenia, osteoporosis, and increased risk of fractures. Although several mechanisms may contribute to skeletal abnormalities in IBD patients, inflammation and inflammatory mediators such as TNF, IL-1β, and IL-6 may be the most critical. It is not clear whether the changes in bone metabolism leading to decreased mineral density are the result of decreased bone formation, increased bone resorption, or both, with varying results reported in experimental models of IBD and in pediatric and adult IBD patients. New data, including our own, challenge the conventional views, and contributes to the unraveling of an increasingly complex network of interactions leading to the inflammation-associated bone loss. Since nutritional interventions (dietary calcium and vitamin D supplementation) are of limited efficacy in IBD patients, understanding the pathophysiology of osteopenia and osteoporosis in Crohn's disease and ulcerative colitis is critical for the correct choice of available treatments or the development of new targeted therapies. In this review, we discuss current concepts explaining the effects of inflammation, inflammatory mediators and their signaling effectors on calcium and phosphate homeostasis, osteoblast and osteoclast function, and the potential limitations of vitamin D used as an immunomodulator and anabolic hormone in IBD.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    URL: Article
    DOI: 10.1152/ajpgi.00496.2010
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2011
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  • 6
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    Molecular mechanism of rat NHE3 gene promoter regulation by sodium butyrate
    American Physiological Society ; 2007
    In:  American Journal of Physiology-Cell Physiology Vol. 293, No. 1 ( 2007-07), p. C64-C74
    Details
    In: American Journal of Physiology-Cell Physiology, American Physiological Society, Vol. 293, No. 1 ( 2007-07), p. C64-C74
    Abstract: Sodium butyrate (NaB) stimulates sodium and water absorption by inducing colonic Na + /H + exchange. NaB induces Na + /H + exchanger (NHE)3 activity and protein and mRNA expression both in vivo and in vitro. Our previously published observations indicated that this induction is Ser/Thr kinase dependent and that NaB-responsive elements were localized within −320/−34 bp of the rat NHE3 promoter. Here we further delineate the mechanism of NaB-mediated NHE3 gene transcription. Transient and stable transfection of Caco-2 cells with NHE3 gene reporter constructs identified Sp binding site SpB at position −58/−55 nt as critical for NaB-mediated induction. Gel mobility shift (GMSA) and DNA affinity precipitation assays indicated NaB-induced binding of Sp3 and decreased binding of Sp1 to SpB element. While no changes in expression of Sp1 or Sp3 were noted, NaB induced phosphorylation of Sp1 and acetylation of Sp3. Sp3 was a more potent inducer of NHE3 gene transcription, which suggested that change in balance, favoring binding of Sp3 to the SpB site, would result in significant increase in NHE3 promoter activity. Small interfering RNA studies in Caco-2 cells and data from NaB-treated SL2 cells used as a reconstitution model confirmed this hypothesis. In addition to the SpB site, which played a permissive role, an upstream novel butyrate response element located at −196/−175 nt was necessary for maximal induction. GMSA identified a protein-DNA complex with a −196/−175 nt probe; this interaction was not affected by NaB treatment, thus suggesting that in response to NaB Sp3 binding to site SpB precedes and results in recruitment of the putative factor to this upstream site.
    Type of Medium: Online Resource
    ISSN: 0363-6143 , 1522-1563
    URL: Article
    DOI: 10.1152/ajpcell.00277.2006
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2007
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  • 7
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    Curcumin inhibits interferon-γ signaling in colonic epithelial cells
    American Physiological Society ; 2012
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 302, No. 1 ( 2012-01), p. G85-G96
    Details
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 302, No. 1 ( 2012-01), p. G85-G96
    Abstract: Curcumin (diferulolylmethane) is an anti-inflammatory phenolic compound found effective in preclinical models of inflammatory bowel diseases (IBD) and in ulcerative colitis patients. Pharmacokinetics of curcumin and its poor systemic bioavailability suggest that it targets preferentially intestinal epithelial cells. The intestinal epithelium, an essential component of the gut innate defense mechanisms, is profoundly affected by IFN-γ, which can disrupt the epithelial barrier function, prevent epithelial cell migration and wound healing, and prime epithelial cells to express major histocompatibility complex class II (MHC-II) molecules and to serve as nonprofessional antigen-presenting cells. In this report we demonstrate that curcumin inhibits IFN-γ signaling in human and mouse colonocytes. Curcumin inhibited IFN-γ-induced gene transcription, including CII-TA, MHC-II genes (HLA-DRα, HLA-DPα1, HLA-DRβ1), and T cell chemokines (CXCL9, 10, and 11). Acutely, curcumin inhibited Stat1 binding to the GAS cis-element, prevented Stat1 nuclear translocation, and reduced Jak1 phosphorylation and phosphorylation of Stat1 at Tyr 701 . Longer exposure to curcumin led to endocytic internalization of IFNγRα followed by lysosomal fusion and degradation. In summary, curcumin acts as an IFN-γ signaling inhibitor in colonocytes with biphasic mechanisms of action, a phenomenon that may partially account for the beneficial effects of curcumin in experimental colitis and in human IBD.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    URL: Article
    DOI: 10.1152/ajpgi.00275.2011
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2012
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  • 8
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    Reduced colonic microbial diversity is associated with colitis in NHE3-deficient mice
    American Physiological Society ; 2013
    In:  American Journal of Physiology-Gastrointestinal and Liver Physiology Vol. 305, No. 10 ( 2013-11-15), p. G667-G677
    Details
    In: American Journal of Physiology-Gastrointestinal and Liver Physiology, American Physiological Society, Vol. 305, No. 10 ( 2013-11-15), p. G667-G677
    Abstract: Chronic inflammation and enteric infections are frequently associated with epithelial Na + /H + exchange (NHE) inhibition. Alterations in electrolyte transport and in mucosal pH associated with inflammation may represent a key mechanism leading to changes in the intestinal microbial composition. NHE3 expression is essential for the maintenance of the epithelial barrier function. NHE3 −/− mice develop spontaneous distal chronic colitis and are highly susceptible to dextran sulfate (DSS)-induced mucosal injury. Spontaneous colitis is reduced with broad-spectrum antibiotics treatment, thus highlighting the importance of the microbiota composition in NHE3 deficiency-mediated colitis. We herein characterized the colonic microbiome of wild-type (WT) and NHE3 −/− mice housed in a conventional environment using 454 pyrosequencing. We demonstrated a significant decrease in the phylogenetic diversity of the luminal and mucosal microbiota of conventional NHE3 −/− mice compared with WT. Rederivation of NHE3 −/− mice from conventional to a barrier facility eliminated the signs of colitis and decreased DSS susceptibility. Reintroduction of the conventional microflora into WT and NHE3 −/− mice from the barrier facility resulted in the restoration of the symptoms initially described in the conventional environment. Interestingly, qPCR analysis of the microbiota composition in mice kept in the barrier facility compared with reconventionalized mice showed a significant reduction of Clostridia classes IV and XIVa. Therefore, the gut microbiome plays a prominent role in the pathogenesis of colitis in NHE3 −/− mice, and, reciprocally, NHE3 also plays a critical role in shaping the gut microbiota. NHE3 deficiency may be a critical contributor to dysbiosis observed in patients with inflammatory bowel disease.
    Type of Medium: Online Resource
    ISSN: 0193-1857 , 1522-1547
    URL: Article
    DOI: 10.1152/ajpgi.00189.2013
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2013
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  • 9
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    Glucocorticoid regulation of the murine PHEX gene
    American Physiological Society ; 2002
    In:  American Journal of Physiology-Renal Physiology Vol. 283, No. 2 ( 2002-08-01), p. F356-F363
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 283, No. 2 ( 2002-08-01), p. F356-F363
    Abstract: The phosphate-regulating gene with homologies to endopeptidases on the X chromosome (PHEX) is a member of the neutral endopeptidase family, which is expressed predominantly on the plasma membranes of mature osteoblasts and osteocytes. Although it is known that the loss of PHEX function results in X-linked hypophosphatemic rickets, characterized by abnormal bone matrix mineralization and renal phosphate wasting, little is known about how PHEX is regulated. We therefore sought to determine whether the murine PHEX gene is regulated by glucocorticoids (GCs), which are known to influence phosphate homeostasis and bone metabolism. Northern blot analysis revealed increased PHEX mRNA expression in GC-treated suckling mice (1.5-fold) and in rat osteogenic sarcoma (UMR-106) cells (2.5-fold). An increase was also seen in PHEX promoter activity in transiently transfected UMR-106 cells with GC treatment. Analysis of nested promoter deletions revealed that an atypical GC response element was located between −337 and −315 bp. Mutational analysis and electrophoretic mobility shift assays further identified −326 to −321 bp as a site involved in GC regulation. Supershift analyses and electrophoretic mobility shift assay competition studies indicated that the core binding factor α1-subunit transcription factor is able to bind to this region and may therefore play a role in the GC response of the murine PHEX gene.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00357.2001
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2002
    detail.hit.zdb_id: 1477287-5
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  • 10
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    Cardiac glycoside downregulates NHE3 activity and expression in LLC-PK 1 cells
    American Physiological Society ; 2006
    In:  American Journal of Physiology-Renal Physiology Vol. 290, No. 5 ( 2006-05), p. F997-F1008
    Details
    In: American Journal of Physiology-Renal Physiology, American Physiological Society, Vol. 290, No. 5 ( 2006-05), p. F997-F1008
    Abstract: Ouabain, a cardiotonic steroid and a specific inhibitor of the Na + -K + -ATPase, has been shown to significantly inhibit transcellular Na + transport without altering the intracellular Na + concentration ([Na + ] i ) in the epithelial cells derived from the renal proximal tubules. We therefore studied whether ouabain affects the activity and expression of Na + /H + exchanger isoform 3 (NHE3) representing the major route of apical Na + reabsorption in LLC-PK 1 cells. Chronic basolateral, but not apical, exposure to low-concentration ouabain (50 and 100 nM) did not change [Na + ] i but significantly reduced NHE3 activity, NHE3 protein, and mRNA expression. Inhibition of c-Src or phosphoinositide 3-kinase (PI3K) with PP2 or wortmannin, respectively, abolished ouabain-induced downregulation of NHE3 activity and mRNA expression. In caveolin-1 knockdown LLC-PK 1 cells, ouabain failed to downregulate NHE3 mRNA expression and NHE3 promoter activity. Ouabain response elements were mapped to a region between −450 and −1,194 nt, where decreased binding of thyroid hormone receptor (TR) and Sp1 to their cognate cis-elements was documented in vitro and in vivo by protein/DNA array analysis, EMSA, supershift, and chromatin immunoprecipitation. These data suggest that, in LLC-PK 1 cells, ouabain-induced signaling through the Na + -K + -ATPase-Src pathway results in decreased Sp1 and TR DNA binding activity and consequently in decreased expression and activity of NHE3. These novel findings may represent the underlying mechanism of cardiotonic steroid-mediated renal compensatory response to volume expansion and/or hypertension.
    Type of Medium: Online Resource
    ISSN: 1931-857X , 1522-1466
    URL: Article
    DOI: 10.1152/ajprenal.00322.2005
    Language: English
    Publisher: American Physiological Society
    Publication Date: 2006
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