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Results for “Mice, Knockout”

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At least 73 records · Page 4Linked to original sources

PubMed2002

Effects of orchiopexy on congenitally cryptorchid insulin-3 knockout mice.

PURPOSE: Insulin-3 (Insl3) knockout mice exhibit isolated, bilateral, high intra-abdominal cryptorchidism. If left in this position until adulthood, these testes will deteriorate to the Sertoli-cell-only state, leading to infertility in 100%. We examined the effect of orchiopexy in this genetically engineered animal model. MATERIALS AND METHODS: A total of 160 testes from 80 male offspring of Insl3 F crosses underwent either no orchiopexy (29 testes), sham surgery (25 testes), 1-stage Fowler-Stephens scrotal orchiopexy (57 testes) or primary orchiopexy into a low abdominal, subcutaneous pouch (49 testes). A group of postoperative mice underwent fertility testing 3 months postoperatively. At 6 to 9 months postoperatively the testes were harvested and histologically analyzed. RESULTS: Testes were atrophic in 100% (25 of 25) of the sham group, 91% (52 of 57) of the Fowler-Stephens orchiopexy group and 33% (16 of 49) of the subcutaneous pouch group (testis weight less than 50 mg.). Fertility testing was done in 30 mice (sham 5, Fowler-Stephens orchiopexy 17 and subcutaneous pouch 8). Infertility was secondary to bilateral testicular atrophy (sham 5 of 5, Fowler-Stephens orchiopexy 13 of 17), spermatogenic maturation arrest (subcutaneous pouch 8 of 8) and ductal obstruction [normal spermatogenesis with epididymis devoid of sperm] (Fowler-Stephens orchiopexy 2 of 17). Fertility with normal spermatogenesis was observed in 2 of 17 Fowler-Stephens orchiopexy mice, both of which were Insl3 knockout mice. CONCLUSIONS: Intrascrotal orchiopexy can rescue these congenitally cryptorchid Insl3 knockout testes from their intra-abdominal fate of Sertoli-cell-only and lead to fertility. The results suggest that orchiopexy has a crucial and central role in preservation of spermatogenesis.

Animals↗

PubMed2004

Catecholamine synthesizing enzymes and their modulation by immobilization stress in knockout mice.

The c-fos knockout mice (c-fos KO) and corticotropin-releasing hormone knockout mice (CRH KO) can serve as interesting models for studying mechanisms involved in response of the organism to stress, focused mainly on the hypothalamic-pituitary-adrenal (HPA) axis and sympathoadrenal system (SAS). The present study focused on the investigation of changes in gene expression of catecholamine biosynthesizing enzymes tyrosine hydroxylase (TH), dopamine-beta-hydroxylase (DBH), and phenylethanolamine N-methyltransferase (PNMT) in adrenal medulla of c-fos KO and CRH KO mice stressed by immobilization. Levels of TH, DBH, and PNMT mRNA were determined by reverse transcription-polymerase chain reaction (RT-PCR). Single immobilization for 2 h significantly increased adrenomedullary TH, DBH, and PNMT mRNA levels in both c-fos KO and wild-type (WT) mice compared to unstressed controls. In CRH KO mice, PNMT gene expression was not increased to the same extent after single, but especially after repeated immobilization as in WT mice, in contrast to TH and DBH mRNA levels. Thus, our data indicate that CRH deficiency can influence the PNMT mRNA level in adrenal medulla during stress, confirming the idea that the HPA axis plays the crucial role in PNMT gene regulation in mice. On the other hand, c-Fos protein probably does not play a crucial role in TH, DBH, and PNMT gene expression in adrenal medulla under stress conditions.

Adrenal Medulla↗

PubMed2000

Effect of intragastric application of N-methylnitrosourea in p53 knockout mice.

Nullizygous p53 knockout (p53(-/-)) mice are highly susceptible to spontaneous tumorigenesis, in particular malignant lymphomas at an early age. Heterozygous p53 knockout (p53(+/-)) mice develop spontaneous tumors less frequently but may show increased susceptibility to chemical carcinogens. In this study, p53(-/-), p53(+/-), and p53 wild-type (p53(+/+)) mice were treated with N-methylnitrosourea (MNU) by gastric intubation (5 microg/g body weight) three times per week for 5 wk, starting at 5-6 wk of age. The surviving mice were killed when they were 56-57 wk old. All eight p53(-/-) mice treated with MNU developed malignant lymphomas with a shorter latent period (mean age = 16.4+/-0.5 wk) than their spontaneous tumors (61%, at age 23.3+/-1.4 wk). In p53(+/-) mice treated with MNU, malignant lymphomas developed at a higher frequency (eight of 27, 30%) than did spontaneous lymphomas (5%). Development of sarcomas in p53(-/-) and p53(+/-) mice was also significantly enhanced by treatment with MNU. All eight thymic lymphomas and three sarcomas in the p53(+/-) mice showed a loss of the remaining wild-type p53 allele. These results indicate that intragastric MNU treatment significantly enhanced spontaneous development of malignant lymphomas and sarcomas in both p53(-/-) and p53(+/-) mice. In the stomachs of 12 p53(+/-) mice, that were killed at the end of the experiment, two adenomas, one carcinoma in situ, and four adenocarcinomas were observed. In the stomachs of 31 p53(+/+) mice, eight adenomas and one carcinoma in situ were detected. The overall incidence of tumorous changes in the stomachs of p53(+/-) (seven of 12, 58%) and p53(+/+) (nine of 31, 29%) mice were not significantly different (P = 0.090). However, adenocarcinomas invading the submucosa were observed in p53(+/-) mice (four of 12, 33%) but not in p53(+/+) mice (zero of 31; P = 0. 004), suggesting a slightly higher susceptibility to gastric carcinogenesis induced by MNU in p53(+/-) mice. Mol. Carcinog. 28:97-101, 2000.

Adenocarcinoma↗

PubMed1998

Lymphokine regulation of activation-induced apoptosis in T cells of IL-2 and IL-2R beta knockout mice.

Recent studies using IL-2R alpha knockout mice have generated conflicting results regarding the hypothesis that IL-2/IL-2R interaction is obligatory for the development of AICD, which plays a central and pivotal role in maintaining peripheral tolerance. A relevant consequence of AICD defect is the demonstrated development of autoimmune lymphoproliferative disease in IL-2, IL-2R alpha, and IL-2R beta knockout mice, but not in IL-4, IL-7, or IL-7R knockout mice. Whether IL-4, IL-7, or IL-15 can provide the required signal for AICD development is addressed here using IL-2 and IL-2R beta knockout mice. Lymph node T cells from knockout mice were stimulated with Con A plus rIL-1 for 3 days and then maintained in high concentrations of rIL-4, rIL-7, or rIL-15 for an additional 3 days before they were subjected to AICD analysis. Our study demonstrates that IL-4, IL-7, and IL-15 can transduce signals critical for AICD development in the absence of IL-2-mediated signals. The requirement for relatively high concentrations of these lymphokines suggests their limited role in maintaining peripheral T cell tolerance, thus explaining the differential expression of autoimmune lymphoproliferative disease in the targeted mutant strains described above.

Animals↗

PubMed1999

Development of Peyer's patches, follicle-associated epithelium and M cell: lessons from immunodeficient and knockout mice.

Studies with immunodeficient and knockout mice have revealed that the development of mucosa-associated lymphoid tissues (MALT) and peripheral lymphoid nodes share common mechanisms, but also require distinct signals. Gene disruption of lymphotoxins or their cognate receptors affects both Peyer's patch and lymph node organogenesis. Disruption of the osteoprotegerin TNF-family member gene does not impair Peyer's patch development, but prevents formation of peripheral lymph nodes. Peyer's patch do not form in mice with a deleted gene encoding a B lymphocyte-specific chemokine receptor, while most peripheral lymph nodes, except inguinal, are normal in numbers and architecture. In B or T lymphocyte-deficient mice, Peyer's patches, with their overlying follicle-associated epithelium (FAE), are present although reduced in number and size. No Peyer's patches develop in RAG deficient mice. Formation of FAE with typical M cells has not been analyzed in these mice. M cell formation requires the close association of immune cells with differentiated enterocytes and their conversion appears to be transcriptionally regulated. The development of MALT, FAE and probably M cells is a multistep process that requires signalling pathways common to all secondary lymphoid tissues, but also MALT-specific factors.

Animals↗

PubMed2006

Dissection of the NF-kappaB signalling cascade in transgenic and knockout mice.

Studies in transgenic and knockout mice have made a major contribution to our current understanding of the physiological functions of the NF-kappaB signalling cascade. The generation and analysis of mice with targeted modifications of individual components of the NF-kappaB pathway tremendously advanced our knowledge of the roles of the NF-kappaB proteins themselves, and also of the many activators and negative regulators of NF-kappaB. These studies have highlighted the complexity of the NF-kappaB system, by revealing the multiple interactions, redundancies, but also diverse functions, performed by the different molecules participating in the regulation of NF-kappaB signalling. Furthermore, inhibition or enforced activation of NF-kappaB in transgenic mice has uncovered the critical roles that NF-kappaB plays in the pathogenesis of various diseases such as liver failure, diabetes and cancer.

Animals↗

PubMed2001

Increased TGF-beta1 in the lungs of asbestos-exposed rats and mice: reduced expression in TNF-alpha receptor knockout mice.

Inhalation of numerous fibrogenic agents causes interstitial pulmonary fibrosis (IPF) in humans and in a number of animal models. Several of these models provide evidence that certain peptide growth factors (GF) are playing a role in the disease process. Transforming growth factor beta 1 (TGF-beta1) is a potent inducer of extracellular matrix production by mesenchymal cells, and we have shown that this peptide is produced in the lung after asbestos exposure. We used in situ hybridization to demonstrate that the mRNA for TGF-beta1 is rapidly expressed post-exposure at sites of initial asbestos-induced lung injury in both rats and mice. The TGF-beta1 is expressed by bronchiolar-alveolar epithelial cells as well as by mesenchymal cells and lung macrophages in exposed animals. Normal rats and mice express little TGF-beta1, as we have demonstrated previously for PDGF-A and -B, TGF-alpha, and TNF-alpha. TGF-beta1 expression is accompanied by collagen and fibronectin production in asbestos-exposed animals. Most interesting, TGF-beta1 expression is largely absent in the lungs of TNF-alpha receptor knockout mice that fail to develop asbestos-induced IPE We have shown previously that the mRNAs and cognate peptides of PDGF-A and -B and TGF-alpha, but not TNF-alpha, are reduced in the fibrosis-resistant knockout mice. In this article, we show that TGF-beta1 is included in this group of cytokines, supporting the postulate that TNF-alpha is necessary for the expression of other, more downstream growth factors, and the consequent development of idiopathic pulmonary fibrosis (IPF).

Administration, Inhalation↗

PubMed1998

Systemic and renal response to salt loading in endothelin-1 knockout mice.

Endothelin-1 (ET-1) knockout mice demonstrate elevated blood pressure, which may be associated with disturbance in central cardiorespiratory regulation. In this study we examined responses to salt loading in ET-1 knockout mice to investigate whether ET-1 is involved in the pathophysiology of salt-sensitive hypertension. Male Edn1+/- heterozygous mice and their wild-type littermates were fed either a high NaCl (8%) or a normal (0.2%) diet for 4 weeks. Systemic blood pressure and tissue ET-1 levels were measured as well as several parameters relating to sodium handling and volume homeostasis. On normal diet, renal ET-1 levels of Edn1+/- mice were about 50% of those of wild-type mice. A high-salt diet caused a significant decrease in renal ET-1 levels by about 50% in both groups. Urine volume, urinary sodium excretion, and FENa in mice on the 8% NaCl diet were significantly higher than those in mice on the 0.2% NaCl diet, whereas there were no differences in circulating plasma volume, serum electrocytes, and creatinine clearance. These responses were similar in Edn1+/- and wild-type mice. Although systemic blood pressure was significantly higher in Edn1+/- mice than in the wild-type, the effect of salt loading on blood pressure was not significant in either Edn1+/- or wild-type mice. We conclude that changes in ET-1 production within a physiologic range do not affect salt sensitivity, although renal ET-1 content is decreased by salt loading.

Animals↗

PubMed1998

Role of IL-10 in inflammation. Studies using cytokine knockout mice.

Interleukin-10 (IL-10) inhibits the synthesis of proinflammatory cytokines known to be involved in fever, including IL-1, IL-6, and tumor necrosis factor-alpha. We hypothesized that IL-10 modulates lipopolysaccharide (LPS)-induced fever in mice. Body temperature was measured by biotelemetry. Swiss Webster mice injected with recombinant murine IL-10 (rmuIL-10) were resistant to fever induced by a low dose of LPS (100 micrograms/kg, i.p.) and to the hypothermic and febrile effects of a high (septic-like) dose of LPS (2.5 mg/kg, i.p.). Injection of rmuIL-10 alone had no effect on afebrile body temperature of Swiss Webster mice. IL-10 knockout mice showed an exacerbated and prolonged fever in response to a low dose of LPS (50 micrograms/kg, i.p.) compared to their wild-type counterparts. These data support the hypothesis that IL-10 acts as an endogenous cryogen during LPS-induced fever in mice.

Analgesics, Non-Narcotic↗

PubMed2003

A1 adenosine receptor knockout mice exhibit increased renal injury following ischemia and reperfusion.

Controversy exists regarding the effect of A1 adenosine receptor (AR) activation in the kidney during ischemia and reperfusion (I/R) injury. We sought to further characterize the role of A1 ARs in modulating renal function after I/R renal injury using both pharmacological and gene deletion approaches in mice. A1 AR knockout mice (A1KO) or their wild-type littermate controls (A1WT) were subjected to 30 min of renal ischemia. Some A1WT mice were subjected to 30 min of renal ischemia with or without pretreatment with 1,3-dipropyl-8-cyclopentylxanthine (DPCPX) or 2-chrolo-cyclopentyladenosine (CCPA), selective A1 AR antagonist and agonist, respectively. Plasma creatinine and renal histology were compared 24 h after renal injury. A1KO mice exhibited significantly higher creatinines and worsened renal histology compared with A1WT controls following renal I/R injury. A1WT mice pretreated with the A1 AR antagonist or agonist demonstrated significantly worsened or improved renal function, respectively, after I/R injury. In addition, A1WT mice pretreated with DPCPX or CCPA showed significantly increased or reduced markers of renal inflammation, respectively (renal myeloperoxidase activity, renal tubular neutrophil infiltration, ICAM-1, TNF-alpha, and IL-1beta mRNA expression), while demonstrating no differences in indicators of apoptosis. In conclusion, we demonstrate that endogenous or exogenous preischemic activation of A1 ARs protects against renal I/R injury in vivo via mechanisms leading to decreased necrosis and inflammation.

Acute Kidney Injury↗

PubMed2000

Neurokinin-1 receptor agonists are involved in mediating neutrophil accumulation in the inflamed, but not normal, cutaneous microvasculature: an in vivo study using neurokinin-1 receptor knockout mice.

We have used tachykinin neurokinin-1 receptor (NK1 receptor) knockout mice to learn of the link between NK1 receptors and neutrophil accumulation in normal naive skin, as compared with inflamed skin. Intradermal substance P (300 pmol) induced edema formation in wild-type mice, but not in NK1 knockout mice, as expected. However, in contrast to IL-1beta (0.3 pmol), substance P did not induce neutrophil accumulation in wild-type mice. IL-1beta-induced neutrophil accumulation was similar in wild-type and knockout mice, but a significant (p < 0.05) contributory effect of added NK1 agonists, which by themselves have no effect on neutrophil accumulation in normal skin, was observed. The results support the concept that NK1 agonists such as substance P cannot act on their own to mediate neutrophil accumulation in naive skin and provide direct evidence that in inflamed skin, under certain circumstances, the NK1 receptor can play a pivotal role in modulating neutrophil accumulation during the ongoing inflammatory process. We investigated responses to two inflammatory stimuli (carrageenin and zymosan). Neutrophil accumulation was significantly attenuated (p < 0.001) in carrageenin- but not zymosan-induced inflammation in NK1 knockout mice. The carrageenin (500 microg)-induced response was inhibited (p < 0.05) by a NK1 receptor antagonist, SR140333 (480 nmol/kg i.v. at -5 min), in the wild-type group. The bradykinin B1 and B2 receptor antagonists (desArg9[Leu8]bradykinin and HOE 140) each reduced neutrophil accumulation to carrageenin in wild-type animals (p < 0.05), but did not cause further reduction of the suppressed response of knockout mice. The results provide evidence that kinin receptors participate in NK1 receptor-dependent neutrophil accumulation in inflamed mouse skin.

Animals↗

PubMed2002

Heightened seizure severity in somatostatin knockout mice.

Patients and experimental models of temporal lobe epilepsy display loss of somatostatinergic neurons in the dentate gyrus. To determine if loss of the peptide somatostatin contributes to epileptic seizures we examined kainate-evoked seizures and kindling in somatostatin knockout mice. Somatostatin knockout mice were not observed to experience spontaneous seizures. Timm staining, acetylcholinesterase histochemistry, and immunocytochemistry for NPY, calbindin, calretinin, and parvalbumin revealed no compensatory changes or developmental abnormalities in the dentate gyrus of somatostatin knockout mice. Optical fractionator counting of Nissl-stained hilar neurons showed similar numbers of neurons in wild type and somatostatin knockout mice. Mice were treated systemically with kainic acid to evoke limbic seizures. Somatostatin knockout mice tended to have a shorter average latency to stage 5 seizures, their average maximal behavioral seizure score was higher, and they tended to be more likely to die than controls. In response to kindling by daily electrical stimulation of the perforant path, to more specifically challenge the dentate gyrus, mean afterdischarge duration in somatostatin knockout mice was slightly longer, but the number of treatments to five stage 4-5 seizures was similar to controls. Although we cannot exclude the possibility of undetected compensatory mechanisms in somatostatin knockout mice, these findings suggest that somatostatin may be mildly anticonvulsant, but its loss alone is unlikely to account for seizures in temporal lobe epilepsy.

Animals↗

PubMed2002

Dentate granule cells in reeler mutants and VLDLR and ApoER2 knockout mice.

We have studied the organization and cellular differentiation of dentate granule cells and their axons, the mossy fibers, in reeler mutant mice lacking reelin and in mutants lacking the reelin receptors very low density lipoprotein receptor (VLDLR) and apolipoprotein E receptor 2 (ApoER2). We show that granule cells in reeler mice do not form a densely packed granular layer, but are loosely distributed throughout the hilar region. Immunolabeling for calbindin and calretinin revealed that the sharp border between dentate granule cells and hilar mossy cells is completely lost in reeler mice. ApoER2/VLDLR double-knockout mice copy the reeler phenotype. Mice deficient only in VLDLR showed minor alterations of dentate organization; migration defects were more prominent in ApoER2 knockout mice. Tracing of the mossy fibers with Phaseolus vulgaris leukoagglutinin and calbindin immunolabeling revealed an irregular broad projection in reeler mice and ApoER2/VLDLR double knockouts, likely caused by the irregular wide distribution of granule cell somata. Mutants lacking only one of the lipoprotein receptors showed only minor changes in the mossy fiber projection. In all mutants, mossy fibers respected the CA3-CA1 border. Retrograde labeling with DiI showed that malpositioned granule cells also projected as normal to the CA3 region. These results indicate that ( 1 ) reelin signaling via ApoER2 and VLDLR is required for the normal positioning of dentate granule cells and (2) the reelin signaling pathway is not involved in pathfinding and target recognition of granule cell axons.

Animals↗

PubMed1999

[Conditional mutagenesis--second generation knockout mice as models for internal diseases].

KNOCKOUT MICE: The generation of knockout mice has largely improved our understanding of the function of a variety of gene products. Gene inactivation experiments in mice have yielded numerous animal models for human diseases, thereby expanding our understanding of the underlying pathophysiological mechanisms. The use of conventional knockout experiments is limited if the phenotyp of gene disruption results in embryonic letality. CONDITIONAL MUTAGENESIS: Conditional mutagenesis aims to overcome this limitation by regional and temporal control of gene inactivation in mice. CRE-LOXP SYSTEM: The bacteriophage-enzyme Cre recognizes loxP-sites in the genome and excises loxP-flanked DNA-regions. Using this system loxP-sites can be introduced into intron regions of a target gene and mice can be created carrying this functional, but loxP-marked gene. When crossed with transgenic mice expressing the Cre-recombinase under control of a tissue-specific and/or inducible promoter the gene will be inactivated in vivo in a timely and regionally controlled fashion.

Animals↗

PubMed2004

The future of wound healing: pursuing surgical models in transgenic and knockout mice.

BACKGROUND: Transgenic and knockout technologies have made determination of the molecular basis of wound healing possible. But there is no comprehensive or standardized approach to the investigation of wound healing in the mouse. A convention is proposed for assessing the multiple dimensions of wound healing. An approach to phenotyping a transgenic or knockout animal in a reproducible fashion is presented using this convention. STUDY DESIGN: Age- and gender-matched wildtype and knockout mice were characterized using six parameters of wound healing: epithelialization, granulation tissue formation, contraction, tensile strength, angiogenesis, and response to ischemia. Six surgical (four standard and two impaired) models were designed and used to quantitate these parameters. These models can be combined to efficiently maximize the data from any given subject. RESULTS: Each model leads to a rapid yield of results, with an average turnover of 4.9 days (range 3 to 7 days), and morbidity and mortality were minimal. A combinatorial approach elucidates the precise wound repair deficit of any subject. A case example is presented. CONCLUSIONS: Six surgical models investigating pertinent wound healing parameters are available. A factorial approach of quantitative wound healing assays maximizes data gathered from any one animal, minimizing the number of transgenic and knockout subjects needed; finely dissects molecular pathways of wound healing; and rapidly phenotypes a particular genetically altered mouse. We propose a standardized approach to wound healing assays that will elucidate critical cellular and molecular mechanisms and potential therapies.

Animals↗

PubMed1997

A proposed test battery and constellations of specific behavioral paradigms to investigate the behavioral phenotypes of transgenic and knockout mice.

Behavioral phenotyping of transgenic and knockout mice requires rigorous, formal analyses. Well-characterized paradigms can be chosen from the established behavioral neuroscience literature. This review describes (1) a series of neurological and neuropsychological tests which are effectively used as a first screen for behavioral abnormalities in mutant mice, and (2) a series of specific behavioral paradigms, clustered by category. Included are multiple paradigms for each category, including learning and memory, feeding, analgesia, aggression, anxiety, depression, schizophrenia, and drug abuse models. Examples are given from the experiences of the authors, in applying these experimental designs to transgenic and knockout mice. Extensive references for each behavioral paradigm are provided, to allow new investigators to access the relevant literature on behavioral methodology.

Animals↗

PubMed2006

Norepinephrine transporter blockade can normalize the prepulse inhibition deficits found in dopamine transporter knockout mice.

Dopamine transporter knockout (DAT KO) mice display deficits in sensorimotor gating that are manifested by reduced prepulse inhibition (PPI) of the acoustic startle reflex. Since PPI deficits may model some of the cognitive dysfunctions identified in certain neuropsychiatric patients, we have studied the effects of transporter blockers on PPI in wild-type and DAT KO mice. Treatments with High dose psychostimulants that block DAT as well as the norepinephrine (NET) and serotonin (SERT) transporters (60 mg/kg cocaine or methylphenidate) significantly impaired PPI in wild-type mice. By contrast, these treatments significantly ameliorated the PPI deficits observed in untreated DAT KO mice. In studies with more selective transport inhibitors, the selective NET inhibitor nisoxetine (10 or 30 mg/kg) also significantly reversed PPI deficits in DAT KO mice. By contrast, while the SERT inhibitor fluoxetine (30 mg/kg) normalized these PPI deficits in DAT KO mice, citalopram (30 or 100 mg/kg) failed to do so. The 'paradoxical' effects of cocaine and methylphenidate in DAT KO mice are thus likely to be mediated, at least in part by the ability of these drugs to block NET, although serotonin systems may also have some role. Together with recent microdialysis data, these results support the hypothesis that prefrontal cortical NET blockade and consequent enhancement of prefrontal cortical extracellular dopamine mediates the reversal of PPI deficits in DAT KO mice.

Acoustic Stimulation↗

PubMed2005

Th1 inflammatory response with altered expression of profibrotic and vasoactive mediators in AT1A and AT1B double-knockout mice.

AT(1) double receptor (AT(1A) and AT(1B)) knockout mice have lower blood pressure, impaired growth, and develop early renal microvascular disease and tubulointerstitial injury. We hypothesized that there would be an increased expression of vasoactive, profibrotic, and inflammatory mediators expressed in the kidneys of AT(1) double-knockout mice. We examined the renal expression of various mediator systems in control (n = 6) vs. double-knockout mice (n = 6) at 3-5 mo of age by real-time PCR, immunohistochemistry, and Western blot analysis. AT(1) double-knockout mice show activation of Th1-dependent pathways (with increased expression of IFN-alpha, IL-2 mRNA) with increased expression of both monocyte (MCP-1 mRNA) and T cell (RANTES mRNA) chemokines, infiltration of CD4(+) and CD11b(+) cells, increased fibrosis-associated mediators (CTGF, TGF-beta and TNF-alpha mRNA) and extracellular matrix (collagens I and III mRNA and protein) deposition compared with controls (P < 0.05 for all markers). These changes were associated with increased mRNA expression of endothelin (ET)-1 and ET-A receptor (P < 0.05), cyclooxygenase (COX)-2/TXA2 synthase (P < 0.05), NADPH oxidase (p40-phox, p67-phox, P < 0.05) and iNOS and nNOS (P < 0.05). COX-2 and nNOS protein were also increased in the kidneys of AT(1) double-knockout mice by Western blot analysis (P < 0.05). Although renin and angiotensinogen mRNA expression were increased in the knockout mice, AT(2) receptor mRNA expression was not significantly different from wild-type mice. In conclusion, the absence of the AT(1) receptor is associated with marked renal alterations in vasoactive, profibrotic, and immune mediators with an inflammatory pattern favoring a Th1 phenotype.

Animals↗