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PubMed2001

Xpa and Xpa/p53+/- knockout mice: overview of available data.

DNA repair deficient Xpa-/- and Xpa-/-/p53+/- knock-out mice in a C57BL/6 genetic background, referred to as respectively the XPA and XPA/p53 model, were investigated in the international collaborative research program coordinated by International Life Sciences Institute (ILSI)/Health and Environmental Science Institute. From the selected list of 21 ILSI compounds, 13 were tested in the XPA model, and 10 in the XPA/p53 model. With one exception, all studies had a duration of 9 months (39 weeks). The observed spontaneous tumor incidence for the XPA model after 9 months was comparable to that of wild-type mice (total 6%). For the XPA/p53 model, this was somewhat higher (9%/13% for males/females). The 3 positive control compounds used, B[a]P, p-cresidine, and 2-AAF, gave positive and consistent tumor responses in both the XPA and XPA/p53 model, but no or lower responses in wild-type mice. From the 13 ILSI compounds tested, the single genotoxic carcinogen (phenacetin) was negative in both the XPA and XPA/p53 model. Positive tumor responses were observed for 4 compounds, the immunosuppressant cyclosporin A, the hormone carcinogens DES and estradiol, and the peroxisome proliferator WY-14,643. Negative results were obtained with 5 other nongenotoxic rodent carcinogens, and 2 noncarcinogens tested. As expected, both DNA repair deficient models respond to genotoxic carcinogens. Combined with previous results, 6 out of 7 (86%) of the genotoxic human and/or rodent carcinogens tested are positive in the XPA model. The positive results obtained with the 4 mentioned nongenotoxic ILSI compounds may point to other carcinogenic mechanisms involved, or may raise some doubts about their true nongenotoxic nature. In general. the XPA/p53 model appears to be more sensitive to carcinogens than the XPA model.

Academies and Institutes↗
PubMedDate not supplied

GLUT4: a key player regulating glucose homeostasis? Insights from transgenic and knockout mice (review).

Studies in which GLUT4 has been overexpressed in transgenic mice provide definitive evidence that glucose transport is rate limiting for muscle glucose disposal. Transgenic overexpression of GLUT4 selectively in skeletal muscle results in increased whole body glucose uptake and improves glucose homeostasis. These studies strengthen the hypothesis that the level of muscle GLUT4 affects the rate of whole body glucose disposal, and underscore the importance of GLUT4 in skeletal muscle for maintaining whole body glucose homeostasis. Studies in which GLUT4 has been ablated or 'knocked-out' provide proof that GLUT4 is the primary effector for mediating glucose transport in skeletal muscle and adipose tissue. Genetic ablation of GLUT4 results in impaired insulin tolerance and defects in glucose metabolism in skeletal muscle and adipose tissue. Because impaired muscle glucose transport leads to reduced whole body glucose uptake and hyperglycaemia, understanding the molecular regulation of glucose transport in skeletal muscle is important to develop effective strategies to prevent or reduce the incidence of Type II diabetes mellitus. In patients with Type II diabetes mellitus, reduced glucose transport in skeletal muscle is a major factor responsible for reduced whole body glucose uptake. Overexpression of GLUT4 in skeletal muscle improves glucose homeostasis in animal models of diabetes mellitus and protects against the development of diabetes mellitus. Thus, GLUT4 is an attractive target for pharmacological intervention strategies to control glucose homeostasis. This review will focus on the current understanding of the role of GLUT4 in regulating cellular glucose uptake and whole body glucose homeostasis.

Animals↗
PubMedDate not supplied

Ins1 gene up-regulated in a beta-cell line derived from Ins2 knockout mice.

The authors have derived a new beta-cell line (betaIns2(-/-lacZ)) from Ins2-/- mice that carry the lacZ reporter gene under control of the Ins2 promoter. betaIns2(-/-lacZ) cells stained positively using anti-insulin antibody, expressed beta-cell-specific genes encoding the transcription factor PDX-1, glucokinase, and Glut-2, retained glucose-responsiveness for insulin secretion, and expressed the lacZ gene. Analysis of Ins1 expression by reverse transcriptase-polymerase chain reaction (RT-PCR) showed that Ins1 transcripts were significantly raised to compensate for the lack of Ins2 transcripts in betaIns2(-/-lacZ) cells, as compared to those found in betaTC1 cells expressing both Ins1/Ins2. Thus, transcriptional up-regulation of the remaining functional insulin gene in Ins2-/- mice could potentially contribute to the beta-cell adaptation exhibited by these mutants, in addition to the increase in beta-cell mass that we previously reported. We have also shown that lacZ expression, as analyzed by determining beta-galactosidase activity, was up-regulated by incubating betaIns2(-/-lacZ) cells with GLP-1 and/or IBMX, 2 known stimulators of insulin gene expression. These cells thus represent a new tool for testing of molecules capable of stimulating Ins2 promoter activity.

Animals↗
PubMed2002

GCAP1 rescues rod photoreceptor response in GCAP1/GCAP2 knockout mice.

Visual transduction in retinal photoreceptors operates through a dynamic interplay of two second messengers, Ca(2+) and cGMP. Ca(2+) regulates the activity of guanylate cyclase (GC) and the synthesis of cGMP by acting on a GC-activating protein (GCAP). While this action is critical for rapid termination of the light response, the GCAP responsible has not been identified. To test if GCAP1, one of two GCAPs present in mouse rods, supports the generation of normal flash responses, transgenic mice were generated that express only GCAP1 under the control of the endogenous promoter. Paired flash responses revealed a correlation between the degree of recovery of the rod a-wave and expression levels of GCAP1. In single cell recordings, the majority of the rods generated flash responses that were indistinguishable from wild type. These results demonstrate that GCAP1 at near normal levels supports the generation of wild-type flash responses in the absence of GCAP2.

Animals↗
PubMed2005

Theophylline pharmacokinetics: comparison of Cyp1a1(-/-) and Cyp1a2(-/-) knockout mice, humanized hCYP1A1_1A2 knock-in mice lacking either the mouse Cyp1a1 or Cyp1a2 gene, and Cyp1(+/+) wild-type mice.

OBJECTIVES: Pharmacokinetics of theophylline was investigated in Cyp1(+/+) wild-type mice, Cyp1a1(-/-) and Cyp1a2(-/-) knockout mice, and humanized hCYP1A1_1A2 mice lacking either the mouse Cyp1a1 or Cyp1a2 gene. METHODS AND RESULTS: Animals received a single dose of theophylline (8 mg/kg i.p.), either alone or pretreated with 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD; 10 microg/kg i.p.) 24 h prior to theophylline. We found that mouse or human CYP1A2 is the predominant enzyme for theophylline metabolism, the contribution of mouse or human CYP1A1 to theophylline metabolism is negligible, and another TCDD-inducible enzyme plays a minor role in 1-methyluric acid and 1,3-dimethyluric acid formation as well as enhanced theophylline clearance from the body. The half-life of elimination from plasma was more than four times longer in Cyp1a2(-/-) than Cyp1(+/+) mice and more than 10 times different after TCDD pretreatment. In humanized hCYP1A1_1A2 mice lacking the mouse Cyp1a2 gene, the half-life of elimination from plasma was two to three times longer than that in Cyp1(+/+) mice and four to five times different after TCDD pretreatment. CONCLUSION: Replacement of mouse Cyp1a2 with a functional human CYP1A2 gene restored the ability to metabolize theophylline, and the metabolism changed to a humanized profile (i.e. 3-methylxanthine formation, not seen in the wild-type mouse). TCDD-pretreated hCYP1A1_1A2 Cyp1a2(-/-) mice exhibited enhanced theophylline metabolism and clearance, due to induction of the human CYP1A2 enzyme. Comparing the hCYP1A1_1A2 Cyp1a2(-/-) and wild-type mice with published clinical studies, we found theophylline clearance to be about 5 times and 12 times, respectively, greater than that reported in humans.

Animals↗
PubMed2006

Evidence from knockout mice against physiologically significant aquaporin 8-facilitated ammonia transport.

Aquaporin (AQP)8-facilitated transport of NH(3) has been suggested recently by increased NH(3) permeability in Xenopus oocytes and yeast expressing human or rat AQP8. We tested the proposed roles of AQP8-facilitated NH(3) transport in mammalian physiology by comparative phenotype studies in wild-type vs. AQP8-null mice. AQP8-facilitated NH(3) transport was confirmed in mammalian cell cultures expressing rat or mouse AQP8, in which the fluorescence of a pH-sensing yellow fluorescent protein was measured in response to ammonia (NH(3)/NH(4)(+)) gradients. Relative AQP8 single-channel NH(3)-to-water permeability was approximately 0.03. AQP8-facilitated NH(3) and water permeability in a native tissue was confirmed in membrane vesicles isolated from testes of wild-type vs. AQP8-null mice, in which BCECF was used as an intravesicular pH indicator. A series of in vivo studies were done in mice, including 1) serum ammonia measurements before and after ammonia infusion, 2) renal ammonia clearance, 3) colonic ammonia absorption, and 4) liver ammonia accumulation and renal ammonia excretion after acute and chronic ammonia loading. Except for a small reduction in hepatic ammonia accumulation and increase in ammonia excretion in AQP8-null mice loaded with large amounts of ammonia, there were no significant differences in wild-type vs. AQP8-null mice. Our results support the conclusion that AQP8 can facilitate NH(3) transport but provide evidence against physiologically significant AQP8-facilitated NH(3) transport in mice.

Ammonia↗
PubMed2005

Transgenic and knockout mice in diabetes research: novel insights into pathophysiology, limitations, and perspectives.

Insulin resistance and type 2 diabetes are serious public health threats. Although enormous research efforts have been focused on the pathogenesis of these diseases, the underlying mechanisms remain only partly understood. Here we review mouse phenotypes resulting from inactivation of molecules responsible for the control of glucose metabolism that have led to novel insights into insulin action and the development of insulin resistance. In addition, more sophisticated strategies to manipulate genes in mice in the future are presented.

Animals↗
PubMed2000

Transfer of CD4(+) T cells aggravates atherosclerosis in immunodeficient apolipoprotein E knockout mice.

BACKGROUND: Atherosclerosis is associated with immune responses to oxidized lipoproteins and certain microorganisms, but the role of specific immunity has remained unclear. METHODS AND RESULTS: To study the role of immunity in atherosclerosis, we crossed atherosclerosis-prone apoE(-/-) mice with immunodeficient scid/scid mice. The offspring showed a 73% reduction in aortic fatty streak lesions when compared with immunocompetent apoE(-/-) mice. Transfer of CD4(+) T cells from apoE(-/-) to immunodeficient apoE(-/-)/scid/scid mice increased lesions by 164%. This was associated with the infiltration of transferred T cells into lesions, increased circulating interferon-gamma levels, and increased I-A expression in lesions. CONCLUSIONS: CD4(+) T cells carry disease-promoting immunity in atherosclerosis.

Animals↗
PubMed1997

Absence of orthogonal arrays in kidney, brain and muscle from transgenic knockout mice lacking water channel aquaporin-4.

Freeze-fracture electron microscopy (FFEM) of kidney collecting duct, muscle, astrocytes in brain, and other mammalian tissues has revealed regular square arrays of intramembrane particles called orthogonal arrays of particles (OAPs). Their possible role in membrane structure and transport have been proposed, and their absence or decrease has been noted in a variety of hereditary and acquired diseases. A transgenic mouse lacking water channel AQP4 was used to show that AQP4 is the OAP protein. FFEM was done on kidney, skeletal muscle, and brain from AQP4 wild-type [+/+], heterozygous [+/-] and knock-out [-/-] mice. The [-/-] mice did not express detectable AQP4 protein, but were grossly indistinguishable from [+/+] mice. FFEM was done on blinded samples of kidney, brain and muscle from 9 mice. In all 6 kidney samples from [+/+] and [+/-] mice, OAPs similar to those in AQP4-transfected CHO cells were found in basolateral membranes of collecting duct principal cells. In all muscle and brain samples from [+/+] and [+/-] mice, OAPs of identical ultrastructure to those in kidney were seen, but in smaller patch sizes. OAPs were not seen in any sample from [-/-] mice. Label-fracture analysis using a peptide-derived AQP4 polyclonal antibody showed immunogold labeling of OAPs in AQP4-expressing CHO cells. These studies provide direct evidence that AQP4 is required for formation of OAPs and is a component of OAPs, thus establishing the identity and function of OAPs.

Animals↗
PubMed1998

[Functional role of angiotensin II predicted from the phenotypes of transgenic and knockout mice].

The renin-angiotensin system, composed of enzymatic and signal-transduction cascades, plays a key role in the regulation of arterial blood pressure and in the development of certain forms of experimental and human hypertension. The products of this system, angiotensin peptides, exert a wide range of physiologically important effects on many tissues, including those of the cardiovascular systems, through their actions on angiotensin receptors. Molecular genetic and transgenic studies have begun to implicate some of the genes encoding components of the renin-angiotensin system in the development of cardiovascular diseases. Here, I review new developments related to the functional role of angiotensin II, an important product of the renin-angiotensin system, by focusing on transgenic approaches, including gene targeting.

Angiotensin II↗