scholarly journals Abnormal fluid homeostasis in apelin receptor knockout mice

2009 ◽  
Vol 202 (3) ◽  
pp. 453-462 ◽  
Author(s):  
Emma M Roberts ◽  
Michael J F Newson ◽  
George R Pope ◽  
Rainer Landgraf ◽  
Stephen J Lolait ◽  
...  
Keyword(s):  
Water Intake ◽  
Urine Volume ◽  
Physiological Role ◽  
Circumventricular Organs ◽  
Free Access ◽  
Drinking Behaviour ◽  
Wild Type ◽  
Fluid Homeostasis ◽  
The Central Nervous System

The apelinergic system, comprised of apelin and its G protein-coupled receptor (APJ; APLNR as given in MGI Database), is expressed within key regions of the central nervous system associated with arginine vasopressin (AVP) synthesis and release as well as in structures involved in the control of drinking behaviour, including the magnocellular neurones of the hypothalamus, circumventricular organs, and the pituitary gland. This localisation is indicative of a possible functional role in fluid homeostasis. We investigated a role for APJ in the regulation of fluid balance using mice deficient for the receptor. Male APJ wild-type and knockout (APJ−/−) mice were housed in metabolic cages to allow determination of water intake and urine volume and osmolality. When provided with free access to water, APJ−/− mice drank significantly less than wild-types, while their urine volume and osmolality did not differ. Water deprivation for 24 h significantly reduced urine volume and increased osmolality in wild-type but not in APJ−/− mice. Baseline plasma AVP concentration increased comparably in both wild-type and APJ−/− mice following dehydration; however, APJ−/− mice were unable to concentrate their urine to the same extent as wild-type mice in response to the V2 agonist desmopressin. Analysis of c-fos (Fos as given in MGI Database) mRNA expression in response to dehydration showed attenuation of expression within the subfornical organ, accentuated expression in the paraventricular nucleus, but no differences in expression in the supraoptic nucleus nor median pre-optic nucleus in APJ−/− mice compared with wild-type. These findings demonstrate a physiological role for APJ in mechanisms of water intake and fluid retention and suggest an anti-diuretic effect of apelin in vivo.

scholarly journals The Centrosomal, Putative Tumor Suppressor Protein TACC2 Is Dispensable for Normal Development, and Deficiency Does Not Lead to Cancer

2004 ◽  
Vol 24 (14) ◽  
pp. 6403-6409 ◽  
Author(s):  
Michael M. Schuendeln ◽  
Roland P. Piekorz ◽  
Christian Wichmann ◽  
Youngsoo Lee ◽  
Peter J. McKinnon ◽  
...  
Keyword(s):  
Tumor Suppressor ◽  
Cell Cycle Progression ◽  
Tumor Development ◽  
Coiled Coil ◽  
Physiological Role ◽  
Tumor Suppressor Protein ◽  
Wild Type ◽  
Mouse Development

ABSTRACT TACC2 is a member of the transforming acidic coiled-coil-containing protein family and is associated with the centrosome-spindle apparatus during cell cycling. In vivo, the TACC2 gene is expressed in various splice forms predominantly in postmitotic tissues, including heart, muscle, kidney, and brain. Studies of human breast cancer samples and cell lines suggest a putative role of TACC2 as a tumor suppressor protein. To analyze the physiological role of TACC2, we generated mice lacking TACC2. TACC2-deficient mice are viable, develop normally, are fertile, and lack phenotypic changes compared to wild-type mice. Furthermore, TACC2 deficiency does not lead to an increased incidence of tumor development. Finally, in TACC2-deficient embryonic fibroblasts, proliferation and cell cycle progression as well as centrosome numbers are comparable to those in wild-type cells. Therefore, TACC2 is not required, nonredundantly, for mouse development and normal cell proliferation and is not a tumor suppressor protein.

Stanniocalcin-1 in the subfornical organ inhibits the dipsogenic response to angiotensin II

2012 ◽  
Vol 303 (9) ◽  
pp. R921-R928 ◽  
Author(s):  
Jason M. Moreau ◽  
Waseem Iqbal ◽  
Jeffrey K. Turner ◽  
Graham F. Wagner ◽  
John Ciriello
Keyword(s):  
Western Blot ◽  
Water Intake ◽  
Body Fluid ◽  
Physiological Role ◽  
Subfornical Organ ◽  
Ang Ii ◽  
Sprague Dawley ◽  
Glycoprotein Hormone ◽  
Fluid Homeostasis ◽  
Body Fluid Homeostasis

Recently, receptors for the calcium-regulating glycoprotein hormone stanniocalcin-1 (STC-1) have been found within subfornical organ (SFO), a central structure involved in the regulation of electrolyte and body fluid homeostasis. However, whether SFO neurons produce STC-1 and how STC-1 may function in fluid homeostasis are not known. Two series of experiments were done in Sprague-Dawley rats to investigate whether STC-1 is expressed within SFO and whether it exerts an effect on water intake. In the first series, experiments were done to determine whether STC-1 was expressed within cells in SFO using immunohistochemistry, and whether protein and gene expression for STC-1 existed in SFO using Western blot and quantitative RT-PCR, respectively. Cells containing STC-1 immunoreactivity were found throughout the rostrocaudal extent of SFO. STC-1 protein expression within SFO was confirmed with Western blot, and SFO was also found to express STC-1 mRNA. In the second series, microinjections (200 nl) of STC-1, ANG II, a combination of the two or the vehicle were made into SFO in conscious, unrestrained rats. Water intake was measured at 0700 for a 1-h period after each injection in animals. Microinjections of STC-1 (17.6 or 176 nM) alone had no effect on water intake compared with controls. However, STC-1 not only attenuated the drinking responses to ANG II for about 30 min, but also decreased the total water intake over the 1-h period. These data suggest that STC-1 within the SFO may act in a paracrine/autocrine manner to modulate the neuronal responses to blood-borne ANG II. These findings also provide the first direct evidence of a physiological role for STC-1 in central regulation of body fluid homeostasis.

scholarly journals Reduced Fertility in Male Mice Deficient in the Zinc Metallopeptidase NL1

2004 ◽  
Vol 24 (10) ◽  
pp. 4428-4437 ◽  
Author(s):  
Mélanie Carpentier ◽  
Christine Guillemette ◽  
Janice L. Bailey ◽  
Guy Boileau ◽  
Lucie Jeannotte ◽  
...  
Keyword(s):  
Male Fertility ◽  
Protein A ◽  
Physiological Role ◽  
Sperm Function ◽  
Secreted Protein ◽  
Wild Type ◽  
The Family ◽  
Fertility Problems ◽  
Targeting Strategy

ABSTRACT Members of the M13 family of zinc metalloendopeptidases have been shown to play critical roles in the metabolism of various neuropeptides and peptide hormones, and they have been identified as important therapeutic targets. Recently, a mouse NL1 protein, a novel member of the family, was identified and shown to be expressed mainly in the testis as a secreted protein. To define its physiological role(s), we used a gene targeting strategy to disrupt the endogenous murine Nl1 gene by homologous recombination and generate Nl1 mutant mice. The Nl1−/− mice were viable and developed normally, suggesting that zygotic expression of Nl1 is not required for development. However, Nl1−/− males produced smaller litters than their wild-type siblings, indicating specific male fertility problems. Reduced fertility may be explained by two impaired processes, decreased egg fertilization and perturbed early development of fertilized eggs. These two phenotypes did not result from gross anatomical modifications of the testis or from impaired spermatogenesis. Basic sperm parameters were also normal. Thus, our findings suggest that one of the roles of NL1 in mice is related to sperm function and that NL1 modulates the processes of fertilization and early embryonic development in vivo.

scholarly journals Systemic PPARγ deletion causes severe disturbance in fluid homeostasis in mice

2015 ◽  
Vol 47 (11) ◽  
pp. 541-547 ◽  
Author(s):  
Li Zhou ◽  
Alexandra Panasiuk ◽  
Maicy Downton ◽  
Daqiang Zhao ◽  
Baoxue Yang ◽  
...  
Keyword(s):  
Weight Loss ◽  
Body Weight Gain ◽  
Collecting Duct ◽  
Urine Volume ◽  
Physiological Role ◽  
Urine Osmolality ◽  
Whole Body ◽  
Peroxisome Proliferator ◽  
Peroxisome Proliferator Activated Receptor ◽  
Fluid Homeostasis

The pharmacological action of peroxisome proliferator-activated receptor (PPAR)γ in promoting sodium and water retention is well documented as highlighted by the major side-effect of body weight gain and edema associated with thiazolidinedione use. However, a possible physiological role of PPARγ in regulation of fluid metabolism has not been reported by previous studies. Here we analyzed fluid metabolism in inducible whole-body PPARγ knockout mice. The null mice developed severe polydipsia and polyuria, reduced urine osmolality, and modest hyperphagia. The phenomenon persisted during 3 days of pair feeding and pair drinking, accompanied by progressive weight loss. After 24 h water deprivation, the null mice had a lower urine osmolality, a higher urine volume, a greater weight loss, and a greater rise in hematocrit than the floxed control. Urinary vasopressin (AVP) excretion was not different between the genotypes under basal condition or after WD. The response of urine osmolality to acute and chronic 1-desamino-8-d-arginine vasopressin treatment was attenuated in the null mice, but the total abundance or phosphorylation of aquaporin 2 (AQP2) in the kidney or AVP-induced cAMP production in inner medullary collecting duct suspensions was unaffected. Overall, PPARγ participates in physiological control of fluid homeostasis through an unknown mechanism involving cAMP/AQP2-independent enhancement of AVP response.

scholarly journals Estrogen Receptor (ER)-β Reduces ERα-Regulated Gene Transcription, Supporting a “Ying Yang” Relationship between ERα and ERβ in Mice

2003 ◽  
Vol 17 (2) ◽  
pp. 203-208 ◽  
Author(s):  
Marie K. Lindberg ◽  
Sofia Movérare ◽  
Stanko Skrtic ◽  
Hui Gao ◽  
Karin Dahlman-Wright ◽  
...  
Keyword(s):  
Estrogen Receptor ◽  
Gene Transcription ◽  
Physiological Role ◽  
Estrogen Receptor Α ◽  
Mrna Levels ◽  
Wild Type ◽  
Ovariectomized Mice ◽  
Adult Bone

Abstract Estrogen is of importance for the regulation of adult bone metabolism. The aim of the present study was to determine the role of estrogen receptor-β (ERβ) in vivo on global estrogen-regulated transcriptional activity in bone. The effect of estrogen in bone of ovariectomized mice was determined using microarray analysis including 9400 genes. Most of the genes (95% = 240 genes) that were increased by estrogen in wild-type (WT) mice were also increased by estrogen in ERβ-inactivated mice. Interestingly, the average stimulatory effect of estrogen on the mRNA levels of these genes was 85% higher in ERβ-inactivated than in WT mice, demonstrating that ERβ reduces estrogen receptor-α (ERα)-regulated gene transcription in bone. The average stimulatory effect of estrogen on estrogen-regulated bone genes in ERα-inactivated mice was intermediate between that seen in WT and ERαβ double-inactivated mice. Thus, ERβ inhibits ERα-mediated gene transcription in the presence of ERα, whereas, in the absence of ERα, it can partially replace ERα. In conclusion, our in vivo data indicate that an important physiological role of ERβ is to modulate ERα-mediated gene transcription supporting a “Ying Yang” relationship between ERα and ERβ in mice.

Abstract 3665: Aggf1 Is Essential for Embryonic and Pathological Angiogenesis

Circulation ◽  
2008 ◽  
Vol 118 (suppl_18) ◽  
Author(s):  
Teng Zhang ◽  
Ping He ◽  
Qing Wang
Keyword(s):  
Tumor Growth ◽  
Physiological Role ◽  
Angiogenic Factor ◽  
Vascular Density ◽  
Wild Type ◽  
Wild Type Littermate ◽  
Gene Trapping ◽  
Pathological Angiogenesis ◽  
Angiogenesis Assay

Backgroud: AGGF1 is a newly identified angiogenic factor associated with vascular disease Klippel-Trenaunay syndrome. AGGF1 has been shown to promote angiogenesis as potently as VEGF in a chicken embryo angiogenesis assay; however, the physiological role of AGGF1 is unknown. Methods and Results: We explored the physiological function of AGGF1 in vivo by employing the gene-trapping strategy in mice. AGGF1−/− mice died by E8.5, suggesting that AGGF1 is essential for embryogenesis. AGGF1 heterozygosity resulted in 31% embryonic lethality. Further macroscopic analysis of embryos at different stages revealed growth retardation and defective vascular development in AGGF1+/− embryos. The major vascular phenotypes included failed development of large vessels and interconnected yolk sac vasculature. Interestingly, decreased phosphorylation of VEGFR2 (Tyr951) was detected in AGGF1+/− embryos compared to the wild type littermate controls, suggesting that AGGF1 may function through VEGFR2-mediated signaling during angiogenesis. Moreover, vascular pathologies of various internal organs were detected in older AGGF1+/− mice. Hemorrhages were frequently noted in brain, spleen and lung, and a chronic inflammatory change was readily detected in lungs in AGGF1+/− mice compared to the littermate controls. Permeability assay further revealed increased vascular permeability in old AGGF1+/− mice (50 – 60 weeks) compared to age- and sex-matched wild-type controls. A tumor angiogenesis model induced by two melanoma cell lines was employed to further assess the angiogenic function of AGGF1 in vivo. Tumor growth was significantly inhibited in AGGF1+/− mice. Histological examinations of the tumor sections revealed markedly reduced microvessel formation in tumors grown in AGGF1+/− mice. Moreover, vascular density quantified after PECAM1 immunostaining showed significant reduction in tumors grown in AGGF1+/− mice. Conclusions: AGGF1 is an important regulator for embryonic angiogenesis and vascular integrity. AGGF1 is also involved in tumor growth and pathological angiogenesis. These results provide for the first time the in vivo experimental evidence that AGGF1 is a potent angiogenic factor essential for both embryonic and pathological angiogenesis.

scholarly journals Immune Response in the Absence of Neurovirulence in Mice Infected with M Protein Mutant Vesicular Stomatitis Virus

2008 ◽  
Vol 82 (18) ◽  
pp. 9273-9277 ◽  
Author(s):  
Maryam Ahmed ◽  
Tracie R. Marino ◽  
Shelby Puckett ◽  
Nancy D. Kock ◽  
Douglas S. Lyles
Keyword(s):  
Central Nervous System ◽  
Immune Response ◽  
Nervous System ◽  
Vesicular Stomatitis Virus ◽  
M Protein ◽  
Wild Type ◽  
Protein Mutants ◽  
The Central Nervous System ◽  
Vesicular Stomatitis

ABSTRACT Matrix (M) protein mutants of vesicular stomatitis virus (VSV), such as rM51R-M virus, are less virulent than wild-type (wt) VSV strains due to their inability to suppress innate immunity. Studies presented here show that when inoculated intranasally into mice, rM51R-M virus was cleared from nasal mucosa by day 2 postinfection and was attenuated for spread to the central nervous system, in contrast to wt VSV, thus accounting for its reduced virulence. However, it stimulated an antibody response similar to that in mice infected with the wt virus, indicating that it has the ability to induce adaptive immunity in vivo without causing disease. These results support the use of M protein mutants of VSV as vaccine vectors.

scholarly journals Coordinated Regulation and Widespread Cellular Expression of Interferon-Stimulated Genes (ISG) ISG-49, ISG-54, and ISG-56 in the Central Nervous System after Infection with Distinct Viruses

2006 ◽  
Vol 81 (2) ◽  
pp. 860-871 ◽  
Author(s):  
Christie Wacher ◽  
Marcus Müller ◽  
Markus J. Hofer ◽  
Daniel R. Getts ◽  
Regina Zabaras ◽  
...  
Keyword(s):  
Central Nervous System ◽  
Nervous System ◽  
Dominant Role ◽  
Lymphocytic Choriomeningitis ◽  
Wild Type ◽  
Cellular Expression ◽  
The Central Nervous System ◽  
The Brain ◽  
Lcmv Infection

ABSTRACT The interferon (IFN)-stimulated genes (ISGs) ISG-49, ISG-54, and ISG-56 are highly responsive to viral infection, yet the regulation and function of these genes in vivo are unknown. We examined the simultaneous regulation of these ISGs in the brains of mice during infection with either lymphocytic choriomeningitis virus (LCMV) or West Nile virus (WNV). Expression of the ISG-49 and ISG-56 genes increased significantly during LCMV infection, being widespread and localized predominantly to common as well as distinct neuronal populations. Expression of the ISG-54 gene also increased but to lower levels and with a more restricted distribution. Although expression of the ISG-49, ISG-54, and ISG-56 genes was increased in the brains of LCMV-infected STAT1 and STAT2 knockout (KO) mice, this was blunted, delayed, and restricted to the choroid plexus, meninges, and endothelium. ISG-56 protein was regulated in parallel with the corresponding RNA transcript in the brain during LCMV infection in wild-type and STAT KO mice. Similar changes in ISG-49, ISG-54, and ISG-56 RNA levels and ISG-56 protein levels were observed in the brains of wild-type mice following infection with WNV. Thus, the ISG-49, ISG-54, and ISG-56 genes are coordinately upregulated in the brain during LCMV and WNV infection; this upregulation, in the case of LCMV, was totally (neurons) or partially (non-neurons) dependent on the IFN-signaling molecules STAT1 and STAT2. These findings suggest a dominant role for the ISG-49, ISG-54, and ISG-56 genes in the host response to different viruses in the central nervous system, where, particularly in neurons, these genes may have nonredundant functions.

scholarly journals Helicobacter pylori Stores Nickel To Aid Its Host Colonization

2012 ◽  
Vol 81 (2) ◽  
pp. 580-584 ◽  
Author(s):  
Stéphane L. Benoit ◽  
Erica F. Miller ◽  
Robert J. Maier
Keyword(s):  
Helicobacter Pylori ◽  
Gastric Mucosa ◽  
Physiological Role ◽  
Wild Type ◽  
Rank Tests ◽  
Content Type ◽  
Host Mouse ◽  
H Pylori ◽  
Very High

ABSTRACTThe transition metal nickel (Ni) is critical for the pathogenicity ofHelicobacter pylori. Indeed the element is a required component of two enzymes, hydrogenase and urease, that have been shown to be important forin vivocolonization of the host gastric mucosa. Urease accounts for up to 10% of the total cellularH. pyloriprotein content, and therefore the bacterial Ni demand is very high.H. pyloripossess two small and abundant histidine-rich, Ni-binding proteins, Hpn and Hpn-like, whose physiological role in the host have not been investigated. In this study, special husbandry conditions were used to control Ni levels in the host (mouse), including the use of Ni-free versus Ni-supplemented food. The efficacy of each diet was confirmed by measuring the Ni concentrations in sera of mice fed with either diet. Colonization levels (based on rank tests) of theΔhpn Δhpn-like double mutants isolated from the mice provided Ni-deficient chow were statistically lower than those for mice given Ni in their diet. In contrast,H. pyloriwild-type colonization levels were similar in both host groups (e.g., regardless of Ni levels). Our results indicate that the gastric pathogenH. pylorican utilize stored Ni via defined histidine-rich proteins to aid colonization of the host.

The atypical chemokine receptor CCX-CKR scavenges homeostatic chemokines in circulation and tissues and suppresses Th17 responses

Blood ◽  
2010 ◽  
Vol 116 (20) ◽  
pp. 4130-4140 ◽  
Author(s):  
Iain Comerford ◽  
Robert J. B. Nibbs ◽  
Wendel Litchfield ◽  
Mark Bunting ◽  
Yuka Harata-Lee ◽  
...  
Keyword(s):  
T Cell ◽  
Immune Responses ◽  
Lymph Nodes ◽  
Chemokine Receptor ◽  
Fold Increase ◽  
Wild Type ◽  
Peripheral Lymph ◽  
The Central Nervous System

Abstract Our previous in vitro studies led to proposals that the atypical chemokine receptor CCX-CKR is a scavenger of CCR7 ligand homeostatic chemokines. In the present study, we generated CCX-CKR−/− mice and confirm this scavenger function in vivo. Compared with wild-type mice, CCX-CKR−/− have a 5-fold increase in the level of CCL21 protein in blood, and 2- to 3-fold increases in CCL19 and CCL21 in peripheral lymph nodes. The effect of these protein increases on immunity was investigated after immunization with MOG35-55 peptide emulsified in complete Freund adjuvant (CFA). The subsequent characteristic paralysis develops with enhanced kinetics and severity in CCX-CKR−/− versus wild-type mice. Despite this effect, antigen-specific immune responses in the draining lymph nodes are diminished in CCX-CKR−/− mice. Instead, the earlier onset of disease is associated with enhanced T-cell priming in the CCX-CKR−/− spleen and a skewing of CD4+ T-cell responses toward Th17 rather than Th1. This observation correlates with increased expression of IL-23 in the CCX-CKR−/− spleen and increased CCL21 levels in the central nervous system postimmunization. The early onset of disease in CCX-CKR−/− mice is reversed by systemic administration of neutralizing anti-CCL21 antibodies. Thus, by regulating homeostatic chemokine bioavailability, CCX-CKR influences the localization, kinetics, and nature of adaptive immune responses in vivo.

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