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  • 1
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    Estrogen and testosterone in concert with EFNB3 regulate vascular smooth muscle cell contractility and blood pressure (2016)
    The American Physiological Society (APS)
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    Publication Date: 2016-04-03
    Description: EPH kinases and their ligands, ephrins (EFNs), have vital and diverse biological functions, although their function in blood pressure (BP) control has not been studied in detail. In the present study, we report that Efnb3 gene knockout (KO) led to increased BP in female but not male mice. Vascular smooth muscle cells (VSMCs) were target cells for EFNB3 function in BP regulation. The deletion of EFNB3 augmented contractility of VSMCs from female but not male KO mice, compared with their wild-type (WT) counterparts. Estrogen augmented VSMC contractility while testosterone reduced it in the absence of EFNB3, although these sex hormones had no effect on the contractility of VSMCs from WT mice. The effect of estrogen on KO VSMC contractility was via a nongenomic pathway involving GPER, while that of testosterone was likely via a genomic pathway, according to VSMC contractility assays and GPER knockdown assays. The sex hormone-dependent contraction phenotypes in KO VSMCs were reflected in BP in vivo. Ovariectomy rendered female KO mice normotensive. At the molecular level, EFNB3 KO in VSMCs resulted in reduced myosin light chain kinase phosphorylation, an event enhancing sensitivity to Ca 2+ flux in VSMCs. Our investigation has revealed previously unknown EFNB3 functions in BP regulation and show that EFNB3 might be a hypertension risk gene in certain individuals.
    Keywords: Vascular Biology and Microcirculation
    Print ISSN: 0363-6135
    Electronic ISSN: 1522-1539
    Topics: Medicine
    Published by The American Physiological Society (APS)
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  • 2
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    Impaired TNF/TNFR2 signaling enhances Th2 and Th17 polarization and aggravates allergic airway inflammation (2017)
    The American Physiological Society (APS)
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    Publication Date: 2017-09-02
    Description: CD4 + T-cell differentiation plays an important role in allergic airway diseases. Tumor necrosis factor receptor 2 (TNFR2) has been shown to regulate CD4 + T-lymphocyte differentiation, but its role in allergic airway inflammation is not clear. Here, we investigated the role of TNFR2 in allergic airway inflammation. The mouse model was generated by immunization with ovalbumin and intranasal administration of TNFR2 antibody. Airway inflammation and CD4 + T-cell differentiation were measured in vivo and in vitro. Inhibited TNFR2 signaling aggravated airway inflammation and increased the expression of inflammatory cytokines (IL-4, IL-5, IL-17, and TNF-α) in serum and bronchoalveolar lavage fluid. Impaired TNFR2 signaling promoted Th2 and Th17 polarization but inhibited Th1 and CD4 + CD25 + T-cell differentiation in vivo. Furthermore, TNFR2 signaling inhibition promoted Th2 and Th17 polarization in vitro, which may occur through the activation of TNF receptor-associated factor 2 and NF-B signaling. Therefore, our findings indicate that impaired TNF/TNFR2 signaling enhances Th2 and Th17 polarization and aggravates allergic airway inflammation.
    Print ISSN: 1040-0605
    Electronic ISSN: 1522-1504
    Topics: Medicine
    Published by The American Physiological Society (APS)
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  • 3
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    Suppression of intestinal calcium entry channel TRPV6 by OCRL, a lipid phosphatase associated with Lowe syndrome and Dent disease (2012)
    The American Physiological Society (APS)
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    Publication Date: 2012-05-16
    Description: Oculocerebrorenal syndrome of Lowe (OCRL) gene product is a phosphatidyl inositol 4,5-bisphosphate [PI( 4 , 5 )P 2 ] 5-phosphatase, and mutations of OCRL cause Lowe syndrome and Dent disease, both of which are frequently associated with hypercalciuria. Transient receptor potential, vanilloid subfamily, subtype 6 (TRPV6) is an intestinal epithelial Ca 2+ channel mediating active Ca 2+ absorption. Hyperabsorption of Ca 2+ was found in patients of Dent disease with increased Ca 2+ excretion. In this study, we tested whether TRPV6 is regulated by OCRL and, if so, to what extent it is altered by Dent-causing OCRL mutations using Xenopus laevis oocyte expression system. Exogenous OCRL decreased TRPV6-mediated Ca 2+ uptake by regulating the function and trafficking of TRPV6 through different domains of OCRL. The PI( 4 , 5 )P 2 5-phosphatase domain suppressed the TRPV6-mediated Ca 2+ transport likely through regulating the PI( 4 , 5 )P 2 level needed for TRPV6 function without affecting TRPV6 protein abundance of TRPV6 at the cell surface. The forward trafficking of TRPV6 was decreased by OCRL. The Rab binding domain in OCRL was involved in regulating the trafficking of TRPV6. Knocking down endogenous X. laevis OCRL by antisense approach increased TRPV6-mediated Ca 2+ transport and TRPV6 forward trafficking. All seven Dent-causing OCRL mutations examined exhibited alleviation of the inhibitory effect on TRPV6-mediated Ca 2+ transport together with decreased overall PI( 4 , 5 )P 2 5-phosphatase activity. In conclusion, OCRL suppresses TRPV6 via two separate mechanisms. The disruption of PI( 4 , 5 )P 2 5-phosphatase activity by Dent-causing mutations of OCRL may lead to increased intestinal Ca 2+ absorption and, in turn, hypercalciuria.
    Print ISSN: 0363-6143
    Electronic ISSN: 1522-1563
    Topics: Medicine
    Published by The American Physiological Society (APS)
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  • 4
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    Disease-causing R1185C mutation of WNK4 disrupts a regulatory mechanism involving calmodulin binding and SGK1 phosphorylation sites (2013)
    The American Physiological Society (APS)
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    Publication Date: 2013-01-02
    Description: The R1185C mutation in WNK4 is associated with pseudohypoaldosteronism type II (PHAII). Unlike other PHAII-causing mutations in the acidic motif, the R1185C mutation is located in the COOH-terminal region of WNK4. The goal of the study is to determine what properties of WNK4 are disrupted by the R1185C mutation. We found that the R1185C mutation is situated in the middle of a calmodulin (CaM) binding site and the mutation reduces the binding of WNK4 to Ca 2+ /CaM. The R1185C mutation is also close to serum- and glucocorticoid-induced protein kinase (SGK1) phosphorylation sites S1190 and S1217. In addition, we identified a novel SGK1 phosphorylation site (S1201) in WNK4, and phosphorylation at this site is reduced by Ca 2+ /CaM. In the wild-type WNK4, the level of phosphorylation at S1190 is the lowest and that at S1217 is the highest. In the R1185C mutant, phosphorylation at S1190 is eliminated and that at S1201 becomes the strongest. The R1185C mutation enhances the positive effect of WNK4 on the Na + -K + -2Cl – cotransporter 2 (NKCC2) as tested in Xenopus laevis oocytes. Deletion of the CaM binding site or phospho-mimicking at two or three of the SGK1 sites enhances the WNK4 effects on NKCC2. These results indicate that the R1185C mutation disrupts an inhibitory domain as part of the suppression mechanism of WNK4, leading to an elevated WNK4 activity at baseline. The presence of CaM binding and SGK1 phosphorylation sites in or close to the inhibitory domain suggests that WNK4 activity is subject to the regulation by intracellular Ca 2+ and phosphorylation.
    Print ISSN: 1931-857X
    Electronic ISSN: 1522-1466
    Topics: Medicine
    Published by The American Physiological Society (APS)
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  • 5
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    Liver X receptor {alpha} induces 17{beta}-hydroxysteroid dehydrogenase-13 expression through SREBP-1c (2017)
    The American Physiological Society (APS)
    Details
    Publication Date: 2017-04-05
    Description: Liver X receptors, including LXRα and LXRβ, are known to be master regulators of liver lipid metabolism. Activation of LXRα increases hepatic lipid storage in lipid droplets (LDs). 17β-Hydroxysteroid dehydrogenase-13 (17β-HSD13), a recently identified liver-specific LD-associated protein, has been reported to be involved in the development of nonalcoholic fatty liver disease. However, little is known about its transcriptional regulation. In the present study, we aimed at determining whether 17β-HSD13 gene transcription is controlled by LXRs. We found that treatment with T0901317, a nonspecific LXR agonist, increased both 17β-HSD13 mRNA and protein levels in cultured hepatocytes. It also significantly upregulated hepatic 17β-HSD13 expression in wild-type (WT) and LXRβ –/– mice but not in LXRα –/– mice. Basal expression of 17β-HSD13 in the livers of LXRα –/– mice was lower than that in the livers of WT and LXRβ –/– mice. Moreover, induction of hepatic 17β-HSD13 expression by T0901317 was almost completely abolished in SREBP-1c –/– mice. Bioinformatics analysis revealed a consensus sterol regulatory element (SRE)-binding site in the promoter region of the 17β-HSD13 gene. A 17β-HSD13 gene promoter-driven luciferase reporter and ChIP assays further confirmed that the 17β-HSD13 gene was under direct control of SREBP-1c. Collectively, these findings demonstrate that LXRα activation induces 17β-HSD13 expression in a SREBP-1c-dependent manner. 17β-HSD13 may be involved in the development of LXRα-mediated fatty liver.
    Print ISSN: 0193-1849
    Electronic ISSN: 1522-1555
    Topics: Medicine
    Published by The American Physiological Society (APS)
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