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1.
Mamm Genome ; 35(2): 149-159, 2024 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-38658415

RESUMO

The petit (pet) locus is associated with dwarfism, testicular anomalies, severe thymic hypoplasia, and high postnatal lethality, which are inherited in autosomal recessive mode of inheritance in rats with a Wistar strain genetic background. Linkage analysis localized the pet locus between 98.7 Mb and 101.2 Mb on rat chromosome 9. Nucleotide sequence analysis identified 2 bp deletion in exon 2 of the Thap4 gene as the causative mutation for pet. This deletion causes a frameshift and premature termination codon, resulting in a truncated THAP4 protein lacking approximately two-thirds of the C-terminal side. Thap4 is expressed in various organs, including the testis and thymus in rats. To elucidate the biological function of THAP4 in other species, we generated Thap4 knockout mice lacking exon 2 of the Thap4 gene through genome editing. Thap4 knockout mice also exhibited dwarfism and small testis but did not show high postnatal lethality. Thymus weights of adult Thap4 knockout male mice were significantly higher compared to wild-type male mice. Although Thap4 knockout male mice were fertile, their testis contained seminiferous tubules with spermatogenesis and degenerative seminiferous tubules lacking germ cells. Additionally, we observed vacuoles in seminiferous tubules, and clusters of cells in the lumen in seminiferous tubules in Thap4 knockout male mice. These results demonstrate that spontaneous mutation of Thap4 gene in rats and knockout of Thap4 gene in mice both cause dwarfism and testicular anomalies. Thap4 gene in rats and mice is essential for normal testicular development, maintaining spermatogenesis throughout the entire region of seminiferous tubules.


Assuntos
Nanismo , Camundongos Knockout , Testículo , Animais , Masculino , Nanismo/genética , Nanismo/patologia , Testículo/metabolismo , Testículo/patologia , Camundongos , Ratos , Mutação , Ratos Wistar
2.
Biology (Basel) ; 10(7)2021 Jul 08.
Artigo em Inglês | MEDLINE | ID: mdl-34356489

RESUMO

The kidneys participate in the regulation of systemic glucose metabolism via gluconeogenesis, insulin degradation, and the tubular reabsorption of glucose. The present study characterized rats from a strain of a novel type 2 diabetes model with enlarged kidneys (DEK). Histological and biochemical analyses of DEK rats were performed to assess the relationships between their kidneys and hyperglycemia. The kidney weight of diabetic DEK (DEK-DM) gradually increased over time from the onset of diabetes, with the glomerular number being higher in DEK-DM than in normal DEK (DEK-cont). A positive correlation between blood glucose level and kidney weight was observed in DEK-DM. The similar glomerular size and single glomerular creatinine clearance in DEK-cont and DEK-DM indicated that glomerular hypertrophy and hyperfiltration were not involved in the renal enlargement. Uninephrectomy (1/2Nx) in DEK-DM resulted in a reduction in blood glucose level at 7-28 post-operation days, with this concentration remaining lower than in Sham group until 84 days post-operation. 1/2Nx also improved systemic conditions, including reduced body weight gain, polyuria, polydipsia, and hyperphagia. Plasma concentrations of Na, total cholesterol, albumin, and total protein were higher, and urinary excretion of glucose, urea nitrogen, and proteins were lower, in the 1/2Nx than in the Sham group. Remnant kidney weight was two-fold higher in the 1/2Nx than in the Sham group 84 days later. In addition, 1/2Nx resulted in renal tubular dilatation but not in the progression of fibrosis or glomerular lesions. Taken together, these findings indicate that enlarged kidneys were associated with the onset of diabetes and with the resistance to diabetic nephropathy in DEK-DM.

3.
PLoS One ; 16(5): e0251135, 2021.
Artigo em Inglês | MEDLINE | ID: mdl-33945582

RESUMO

BACKGROUND: Sodium-glucose cotransporter 2 (SGLT2) inhibitors are widely used to reduce hyperglycemia. The present study investigated the effects of a SGLT2 inhibitor, empagliflozin, on hyperglycemia in a novel rat model of non-obesity type 2 diabetes with enlarged kidney (DEK). METHODS: Male DEK rats with non-fasting blood glucose concentrations ≤300 mg/dl and >300 mg/dl were classified as nondiabetic and diabetic, respectively. Groups of nondiabetic (control) and diabetic (DM-cont) rats were fed standard chow for 12 weeks, whereas another group of diabetic (DM-empa) rats was fed standard chow containing empagliflozin (300 mg/kg/day) for 12 weeks. Blood glucose, body weight, glucose tolerance, food and water intake, urinary volume, plasma and urinary biochemical parameters, and bone mineral density were measured, and their kidneys and pancreas histologically analyzed. RESULTS: Treatment with empagliflozin reduced blood glucose concentration and food intake in diabetic rats, but inhibited loss of adeps renis and led to body weight gain. Empagliflozin attenuated polyuria and polydipsia but increased plasma concentrations of total cholesterol, sodium and total protein toward normal level. Empagliflozin also significantly reduced urinary excretion of proteins and electrolytes and restored bone mineral density and plasma concentrations of valine and isoleucine to normal levels. Moreover, dilation of renal tubules and kidney enlargement were not attenuated in the DM-empa group. CONCLUSION: The response of DEK rats to empagliflozin differed from that of other diabetic animal models, suggesting that DEK rats have unique characters for studying and evaluating the multiple biological effects of SGLT2 inhibitors. These findings also indicted that empagliflozin could ameliorate systemic metabolism and improve renal tubule function in diabetic condition.


Assuntos
Compostos Benzidrílicos/farmacologia , Diabetes Mellitus Experimental/tratamento farmacológico , Glucosídeos/farmacologia , Nefropatias/tratamento farmacológico , Rim/efeitos dos fármacos , Animais , Glicemia/efeitos dos fármacos , Diabetes Mellitus Experimental/metabolismo , Diabetes Mellitus Tipo 2/tratamento farmacológico , Modelos Animais de Doenças , Hiperglicemia/tratamento farmacológico , Hiperglicemia/metabolismo , Rim/metabolismo , Nefropatias/metabolismo , Masculino , Ratos , Transportador 2 de Glucose-Sódio/metabolismo , Inibidores do Transportador 2 de Sódio-Glicose/farmacologia
4.
J Histochem Cytochem ; 69(4): 257-270, 2021 04.
Artigo em Inglês | MEDLINE | ID: mdl-33565365

RESUMO

A well-known putative tumor suppressor WW domain-containing oxidoreductase (Wwox) is highly expressed in hormonally regulated tissues and is considered important for the normal development and function of reproductive organs. In this study, we investigated the cellular and subcellular localization of Wwox in normal testes during postnatal days 0-70 using Western blotting and immunohistochemistry. Wwox is expressed in testes at all ages. Immunohistochemistry showed that fetal-type and adult-type Leydig cells, immature and mature Sertoli cells, and germ cells (from gonocytes to step 17 spermatids) expressed Wwox except peritubular myoid cells, step 18-19 spermatids, and mature sperm. Wwox localized diffusely in the cytoplasm with focal intense signals in all testicular cells. These signals gradually condensed in germ cells with their differentiation and colocalized with giantin for cis-Golgi marker and partially with golgin-97 for trans-Golgi marker. Biochemically, Wwox was detected in isolated Golgi-enriched fractions. But Wwox was undetectable in the nucleus. This subcellular localization pattern of Wwox was also confirmed in single-cell suspension. These findings indicate that Wwox is functional in most cell types of testis and might locate into Golgi apparatus via interaction with Golgi proteins. These unique localizations might be related to the function of Wwox in testicular development and spermatogenesis.


Assuntos
Espermatogênese/genética , Testículo/química , Proteínas Supressoras de Tumor/análise , Proteínas Supressoras de Tumor/genética , Oxidorredutase com Domínios WW/análise , Oxidorredutase com Domínios WW/genética , Animais , Imuno-Histoquímica , Masculino , Ratos , Testículo/citologia , Testículo/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Oxidorredutase com Domínios WW/metabolismo
5.
J Vet Med Sci ; 82(11): 1585-1588, 2020 Nov 12.
Artigo em Inglês | MEDLINE | ID: mdl-32921658

RESUMO

The aim of this study was to examine whether 2.16% hypertonic saline solution (HSS) is useful for the treatment of diarrheic calves with hyponatremia. Eleven of 13 female Holstein calves exhibiting moderate diarrhea and hyponatremia received 1,250 ml of 2.16% HSS over 15 min regardless of body weight. The remaining two calves that were unable to stand and had severe hyponatremia received 2,500 ml of 2.16% HSS intravenously over 30 min. As a result, hyponatremia in all diarrheic calves was significantly improved by the administration of 2.16% HSS from 122.2 ± 7.0 mEq/l at pre to 134.8 ± 3.7 mEq/l at post, which was above the threshold of 132 mEq/l for hyponatremia. Therefore, 2.16% HSS may be useful for hyponatremia in calves with diarrhea.


Assuntos
Doenças dos Bovinos , Hiponatremia , Animais , Bovinos , Doenças dos Bovinos/tratamento farmacológico , Diarreia/tratamento farmacológico , Diarreia/veterinária , Feminino , Hiponatremia/tratamento farmacológico , Hiponatremia/veterinária , Solução Salina Hipertônica/uso terapêutico , Sódio
6.
Front Neurosci ; 14: 644, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32581702

RESUMO

Mutations in the WWOX gene cause a broad range of ultra-rare neurodevelopmental and brain degenerative disorders, associated with a high likelihood of premature death in animal models as well as in humans. The encoded Wwox protein is a WW domain-containing oxidoreductase that participates in crucial biological processes including tumor suppression, cell growth/differentiation and regulation of steroid metabolism, while its role in neural development is less understood. We analyzed the exomes of a family affected with multiple pre- and postnatal anomalies, including cerebellar vermis hypoplasia, severe neurodevelopmental impairment and refractory epilepsy, and identified a segregating homozygous WWOX mutation leading to a premature stop codon. Abnormal cerebral cortex development due to a defective architecture of granular and molecular cell layers was found in the developing brain of a WWOX-deficient human fetus from this family. A similar disorganization of cortical layers was identified in lde/lde rats (carrying a homozygous truncating mutation which disrupts the active Wwox C-terminal domain) investigated at perinatal stages. Transcriptomic analyses of Wwox-depleted human neural progenitor cells showed an impaired expression of a number of neuronal migration-related genes encoding for tubulins, kinesins and associated proteins. These findings indicate that loss of Wwox may affect different cytoskeleton components and alter prenatal cortical development, highlighting a regulatory role of the WWOX gene in migrating neurons across different species.

7.
J Diabetes Res ; 2019: 8153140, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31467929

RESUMO

A variety of animal models of diabetes mellitus (DM) are required to study the genetics and pathophysiology of DM. We established a novel rat strain showing nonobese type 2 diabetes with enlarged kidneys from the LEA.PET-pet congenic strain and named it Diabetes with Enlarged Kidney (DEK). The body growth of DEK affected rats was similar to that of normal rats before the development of DM but was attenuated with the deterioration of DM. There was a marked difference in the etiology of DEK by gender: DM phenotypes including polyuria, polydipsia, and hyperglycemia (nonfasting blood glucose over 300 mg/dl) were found in male rats aged over 10 weeks but not in female rats. The cumulative incidence of DM in DEK males at the age of 30 weeks was 44.8%. Oral glucose tolerance tests showed glucose intolerance and decreased insulin secretion in response to glucose loading in affected males, features which were exacerbated with age. Affected males exhibited disorganized architecture of pancreatic islets, decreased numbers of ß cells, and markedly decreased expression of insulin, despite no pathological findings of hemorrhage or infiltration of inflammatory cells in the pancreatic islet. Age-related islet fibrosis appeared similar in normal and affected males. Affected males also showed enlarged kidneys with dilation of renal tubules in both the cortex and medulla, but no obvious glomerular lesions typical of diabetic nephropathy (DN) at the age of 30 weeks. Plasma levels of urea nitrogen and creatinine were normal, but hypoalbuminemia was detected. These pathophysiological features in affected males indicated that their renal function was almost maintained despite severe DM. Taken together, these findings indicate that the affected males of the DEK strain are a novel nonobese type 2 diabetes rat model useful for studying the mechanisms underlying ß cell loss and identifying genetic factors protective against DN.


Assuntos
Diabetes Mellitus Experimental/complicações , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/patologia , Nefropatias Diabéticas/etiologia , Rim/patologia , Animais , Animais Congênicos , Glicemia/análise , Glicemia/metabolismo , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Tipo 2/sangue , Diabetes Mellitus Tipo 2/complicações , Nefropatias Diabéticas/sangue , Nefropatias Diabéticas/patologia , Feminino , Teste de Tolerância a Glucose , Hiperglicemia/complicações , Hiperglicemia/patologia , Hipertrofia/sangue , Hipertrofia/etiologia , Masculino , Polidipsia/etiologia , Polidipsia/patologia , Poliúria/etiologia , Poliúria/patologia , Ratos , Ratos Endogâmicos
8.
Int J Mol Sci ; 20(14)2019 Jul 23.
Artigo em Inglês | MEDLINE | ID: mdl-31340538

RESUMO

WW domain-containing oxidoreductase (Wwox) is a putative tumor suppressor. Several germline mutations of Wwox have been associated with infant neurological disorders characterized by epilepsy, growth retardation, and early death. Less is known, however, about the pathological link between Wwox mutations and these disorders or the physiological role of Wwox in brain development. In this study, we examined age-related expression and histological localization of Wwox in forebrains as well as the effects of loss of function mutations in the Wwox gene in the immature cortex of a rat model of lethal dwarfism with epilepsy (lde/lde). Immunostaining revealed that Wwox is expressed in neurons, astrocytes, and oligodendrocytes. lde/lde cortices were characterized by a reduction in neurite growth without a reduced number of neurons, severe reduction in myelination with a reduced number of mature oligodendrocytes, and a reduction in cell populations of astrocytes and microglia. These results indicate that Wwox is essential for normal development of neurons and glial cells in the cerebral cortex.


Assuntos
Sistemas de Transporte de Aminoácidos Acídicos/deficiência , Antiporters/deficiência , Córtex Cerebral/metabolismo , Nanismo/genética , Epilepsia/genética , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/genética , Doenças Mitocondriais/genética , Neurogênese/genética , Transtornos Psicomotores/genética , Proteínas Supressoras de Tumor/genética , Oxidorredutase com Domínios WW/genética , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/genética , 2',3'-Nucleotídeo Cíclico 3'-Fosfodiesterase/metabolismo , Proteína da Polipose Adenomatosa do Colo/genética , Proteína da Polipose Adenomatosa do Colo/metabolismo , Sistemas de Transporte de Aminoácidos Acídicos/genética , Sistemas de Transporte de Aminoácidos Acídicos/metabolismo , Animais , Antiporters/genética , Antiporters/metabolismo , Astrócitos/metabolismo , Astrócitos/patologia , Contagem de Células , Córtex Cerebral/crescimento & desenvolvimento , Córtex Cerebral/patologia , Modelos Animais de Doenças , Nanismo/metabolismo , Nanismo/patologia , Epilepsia/metabolismo , Epilepsia/patologia , Regulação da Expressão Gênica no Desenvolvimento , Mutação em Linhagem Germinativa , Proteína Glial Fibrilar Ácida/genética , Proteína Glial Fibrilar Ácida/metabolismo , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/metabolismo , Doenças Desmielinizantes Hereditárias do Sistema Nervoso Central/patologia , Masculino , Doenças Mitocondriais/metabolismo , Doenças Mitocondriais/patologia , Proteína Básica da Mielina/genética , Proteína Básica da Mielina/metabolismo , Neurônios/metabolismo , Neurônios/patologia , Oligodendroglia/metabolismo , Oligodendroglia/patologia , Prosencéfalo/crescimento & desenvolvimento , Prosencéfalo/metabolismo , Prosencéfalo/patologia , Transtornos Psicomotores/metabolismo , Transtornos Psicomotores/patologia , Ratos , Ratos Transgênicos , Transdução de Sinais , Proteínas Supressoras de Tumor/deficiência , Oxidorredutase com Domínios WW/deficiência
9.
Biochem Biophys Res Commun ; 499(3): 459-465, 2018 05 15.
Artigo em Inglês | MEDLINE | ID: mdl-29577904

RESUMO

Extracellular matrix (ECM) constitutes a proper micro-environment for cell proliferation, migration and differentiation, as well as playing pivotal roles in developmental processes including endochondral ossification. Cartilage ECM is mainly composed of fibrous proteins, including collagen, proteoglycan, and hyaluronan. Because almost all ECM components are transported by intracellular vesicular transport systems, molecules that mediate vesicle transport are also important for endochondral ossification. Giantin, encoded by the Golgb1 gene, is a tethering factor for coatomer 1 (COPI) vesicles and functions in the cis-medial Golgi compartments. An insertion mutation in the Golgb1 gene, resulting in a lack of giantin protein expression, has been detected in ocd/ocd rats that exhibit a pleiotropic phenotype including osteochondrodysplasia. To reveal the function of giantin in chondrogenesis, the present study assessed the effects of loss of giantin expression on cartilage ECM and Golgi morphology. Giantin was expressed in normal, but not in ocd/ocd, chondrocytes in the epiphyseal areas of embryonic femurs, whereas GM130 was expressed in both normal and ocd/ocd chondrocytes. The staining intensities of safranin O and azan (aniline blue) were reduced and enhanced, respectively, in epiphyseal cartilage of ocd/ocd femurs. Immunostaining showed that levels of type II collagen and fibronectin were comparable in normal and ocd/ocd cartilage. Levels of type XI collagen were higher, while levels of aggrecan, link protein and hyaluronan were lower, in ocd/ocd than in normal cartilage, although semi-quantitative RT-PCR showed similar levels of type XI collagen, aggrecan and link protein mRNAs in normal and ocd/ocd cartilage. Isolated chondrocytes of ocd/ocd and normal rats showed similar immunostaining patterns for cis-, medial-, and trans-Golgi marker proteins, whereas monolayers of ocd/ocd chondrocytes showed reduced levels of aggrecan and link protein and increased level of type XI collagen in spite of similar transcripts levels. These findings suggest that giantin plays a pivotal role in coordinated production of aggrecan, link protein and type XI collagen in chondrocytes, and that loss of giantin causes osteochondrodysplasia with disturbance of these ECM components.


Assuntos
Agrecanas/metabolismo , Condrogênese , Colágeno Tipo XI/metabolismo , Proteínas da Matriz Extracelular/metabolismo , Proteínas de Membrana/metabolismo , Proteoglicanas/metabolismo , Animais , Autoantígenos/metabolismo , Cartilagem/metabolismo , Proliferação de Células , Separação Celular , Condrócitos/citologia , Condrócitos/metabolismo , Matriz Extracelular/metabolismo , Feminino , Fêmur/metabolismo , Complexo de Golgi/metabolismo , Proteínas da Matriz do Complexo de Golgi , Fenótipo , Transporte Proteico , Ratos
10.
Biochem Biophys Res Commun ; 486(4): 958-964, 2017 05 13.
Artigo em Inglês | MEDLINE | ID: mdl-28351621

RESUMO

Male hypogonadism (hgn/hgn) rats show testicular hypoplasia accompanied by dysplastic development of seminiferous tubules due to loss-of-function mutation of the gene encoding Astrin, which is required for mitotic progression in the division cycle of HeLa cells. In the present study, we examined the cytological base leading to the decrease of Sertoli cells in hgn/hgn testes. In hgn/hgn testes on postnatal day 3, anti-phospho-histone H3 (Ser10) (pH3)-positive mitotic phase and TUNEL-positive apoptosis increased in GATA4-positive Sertoli cells. Isolated immature Sertoli cells from hgn/hgn testes showed increased pH3-assessed mitotic index accompanied by decreased 5-bromo-2'-deoxyuridine-incorporation and increased TUNEL-positive apoptosis, suggesting mitotic delay and cell death. In the visualization of mitotic progression by nocodazole (NOC)-mediated cell cycle arrest and subsequent release, hgn/hgn rat-derived Sertoli cells failed to make the transition from prometaphase to metaphase, and the cells with micronuclei and TUNEL-positive cells gradually increased in a time-dependent manner. Western blot analysis detected ≈142 kDa protein expected as Astrin in extracts of +/+ and +/hgn testes and cultured normal Sertoli cells but not in extracts of hgn/hgn testes. CLASP1 was detected in extracts of both normal and hgn/hgn testes, whereas it was localized in kinetochore of normal mitotic Sertoli cells but diffused in cytoplasm of hgn/hgn Sertoli cells. These results indicate that Astrin is required for normal mitotic progression in immature Sertoli cells and that the most severe type of testicullar dysplasia in hgn/hgn rats is caused by mitotic cell death of immature Sertoli cells due to lack of Astrin.


Assuntos
Azul Alciano/metabolismo , Apoptose/fisiologia , Cinetocoros/metabolismo , Proteínas Associadas aos Microtúbulos/metabolismo , Mitose/fisiologia , Fenazinas/metabolismo , Fenotiazinas/metabolismo , Resorcinóis/metabolismo , Células de Sertoli/fisiologia , Animais , Núcleo Celular/metabolismo , Células Cultivadas , Masculino , Camundongos Endogâmicos , Ratos
11.
J Vet Med Sci ; 79(3): 593-601, 2017 Mar 23.
Artigo em Inglês | MEDLINE | ID: mdl-28190822

RESUMO

Recent studies have shown that phloridzin, an inhibitor of sodium-glucose cotransporter (SGLT), strongly decreases high K+-induced contraction in phasic muscle, such as tenia coli, but slightly affects tonic muscle, such as trachea . In this study, we examined the inhibitory mechanism of phloridzin on high K+-induced muscle contraction in rat ileum, a phasic muscle. Phloridzin inhibited the high K+-induced contraction in the ileum and the aorta, and the relaxing effect of phloridzin at 1 mM in the ileum was approximately five-fold more potent than that in the aorta. The expression of SGLT1 mRNA in the ileum was higher than that of the aorta. Phloridzin significantly inhibited NADH/NAD ratio and phosphocreatine (PCr) content in the ileum; however, application of pyruvate recovered the inhibition of contraction and PCr content, but had no effect on ratio of NADH/NAD. High K+ increased 2-(N (7-nitrobenz-2-oxa-1,3-diazol-4-yl) amino)-2-deoxyglucose (2-NBDG) uptake in ileal smooth muscle cells, and phloridzin inhibited the increase in a concentration-dependent manner. These results suggest that phloridzin inhibits high K+-induced contraction because of the inhibition of energy metabolism via the inhibition of SGLT1.


Assuntos
Íleo/efeitos dos fármacos , Florizina/farmacologia , Potássio/metabolismo , Transportador 1 de Glucose-Sódio/antagonistas & inibidores , Animais , Íleo/fisiologia , Masculino , Contração Muscular/efeitos dos fármacos , Músculo Liso/efeitos dos fármacos , Músculo Liso/fisiologia , Ratos Wistar
12.
Exp Toxicol Pathol ; 69(5): 245-258, 2017 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-28185787

RESUMO

A congenital reduction in the number of nephrons is a critical risk factor for both onset of chronic kidney disease (CKD) and its progression to end-stage kidney disease (ESKD). Hypoplastic kidney (HPK) rats have only about 20% of the normal number of nephrons and show progressive CKD. This study used an immunohistological method to assess glomerular and interstitial pathogenesis in male HPK rats aged 35-210days. CD68 positive-macrophages were found to infiltrate into glomeruli in HPK rats aged 35 and 70days and to infiltrate into interstitial tissue in rats aged 140 and 210days. HPK rats aged 35 and 70days showed glomerular hypertrophy, loss of normal linear immunostaining of podocine, and increased expression of PDGFr-ß, TGF-ß, collagens, and fibronectin, with all of these alterations gradually deteriorating with age. α-SMA-positive myofibroblasts were rarely detected in glomerular tufts, whereas α-SMA-positive glomerular parietal epithelium (GPE) cells were frequently observed along Bowman's capsular walls. The numbers of PDGFr-ß-positive fibroblasts in interstitial tissue were increased in rats aged 35days and older, whereas interstitial fibrosis, characterized by the increased expression of tubular PDGF-BB, the appearance of myofibroblasts doubly positive for PDGFr-ß and α-SMA, and increased expression of collagens and fibronectin, were observed in rats aged 70 and older. These results clearly indicate that congenital CKD with only 20% of nephrons cause renal fibrosis in rats.


Assuntos
Insuficiência Renal Crônica/congênito , Insuficiência Renal Crônica/patologia , Animais , Modelos Animais de Doenças , Progressão da Doença , Fibrose/patologia , Masculino , Néfrons/patologia , Ratos
13.
Comp Med ; 66(1): 10-20, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26884405

RESUMO

Renal hypoplasia due to a congenitally reduced number of nephrons progresses to chronic kidney disease and may cause renal anemia, given that the kidneys are a major source of erythropoietin in adults. Hypoplastic kidney (HPK) rats have only about 20% of the normal number of nephrons and develop CKD. This study assessed the renal function and hematologic changes in HPK rats from 70 to 210 d of age. HPK rats demonstrated deterioration of renal excretory function, slightly macrocytic erythropenia at all days examined, age-related increases in splenic hemosiderosis accompanied by a tendency toward increased hemolysis, normal plasma erythropoietin levels associated with increased hepatic and decreased renal erythropoietin production, and maintenance of the response for erythropoietin production to hypoxic conditions, with increased interstitial fibrosis at 140 d of age. These results indicate that increases in splenic hemosiderosis and the membrane fragility of RBC might be associated with erythropenia and that hepatic production of erythropoietin might contribute to maintaining the blood Hgb concentration in HPK rats.


Assuntos
Anemia/fisiopatologia , Nefropatias/fisiopatologia , Rim/fisiopatologia , Insuficiência Renal Crônica/fisiopatologia , Fatores Etários , Anemia/sangue , Anemia/etiologia , Animais , Biomarcadores/sangue , Proteínas de Transporte/genética , Modelos Animais de Doenças , Progressão da Doença , Eritrócitos/metabolismo , Eritrócitos/patologia , Eritropoetina/sangue , Fibrose , Predisposição Genética para Doença , Hemólise , Hemossiderose/sangue , Hemossiderose/etiologia , Hemossiderose/fisiopatologia , Ferro/sangue , Rim/anormalidades , Rim/metabolismo , Nefropatias/sangue , Nefropatias/congênito , Masculino , Mutação , Fragilidade Osmótica , Fenótipo , Ratos , Ratos Endogâmicos , Insuficiência Renal Crônica/sangue , Insuficiência Renal Crônica/etiologia , Baço/metabolismo , Baço/patologia
14.
Aging (Albany NY) ; 8(1): 62-76, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26789258

RESUMO

Telomere shortening occurs when cells divide, both in vitro and in vivo. On the other hand, telomerase is able to maintain telomere length in cells by adding TTAGGG repeats to the ends of telomeres. However, the interrelationships existing among telomere length, telomerase activity and growth in vertebrates remain to be clarified. In the present study we measured telomere length (terminal restriction fragment length), telomerase activity and body growth of Oryzias latipes from the embryo stage until senescence. During the rapid growth stage (age 0-7 months), telomeres shortened in parallel with decreasing telomerase activity. Then, during adolescence (age 7 months - 1 year), telomeres lengthened quickly as growth slowed and telomerase activity increased. In the adult stage (age 1-4 years) characterized by little growth, telomerase activity decreased gradually and telomeres shortened. Our data indicate that telomere attrition and restoration are linked to growth and telomerase activity, and suggest that critical loss of telomere homeostasis is associated with mortality in this animal.


Assuntos
Proteínas de Peixes/metabolismo , Oryzias/metabolismo , Telomerase/metabolismo , Homeostase do Telômero , Encurtamento do Telômero , Telômero/metabolismo , Fatores Etários , Animais , Cinética , Estágios do Ciclo de Vida , Oryzias/genética , Oryzias/crescimento & desenvolvimento , Telômero/genética
15.
Comp Med ; 64(1): 34-43, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24512959

RESUMO

To study spontaneous intraocular hemorrhage in rats during postnatal ocular development and to elucidate the underlying mechanism, postnatal ocular development in the albino Wistar Hannover (WH) and Sprague-Dawley (SpD) and pigmented Long-Evans (LE) strains was analyzed. Pups (n = 2 to 5) from each strain were euthanized daily on postnatal days (PND) 0 through 21 and their eyes examined macroscopically and histologically; similar analyses were performed in 26 to 39 additional WH pups daily from PND 7 to 14. At necropsy, ring-shaped red regions and red spots were present in the eyes of WH and SpD rats. These lesions were attributed histologically to hemorrhage of the tunica vasculosa lentis or of the retina, choroid, and hyaloid artery, respectively. Similar intraocular hemorrhages occurred in LE rats, although the macroscopic alterations found in WH and SpD rats were not present in this strain. Among the 3 strains evaluated, the incidence of the intraocular hemorrhage was highest in WH rats. We here showed that intraocular hemorrhage occurs spontaneously during normal ocular development in rats regardless of the strain; however, the region, degree, and incidence of intraocular hemorrhage differ among strains. Hemorrhage in the tunica vasculosa lentis and hyaloid artery may result from the leakage of erythrocytes from the temporary vasculature of these tissues during regression. The mechanisms underlying hemorrhage in the retina and choroid remain unclear. To our knowledge, this report is the first to describe the spontaneous intraocular hemorrhage that occurs during postnatal ocular development in rats.


Assuntos
Hemorragia da Coroide/veterinária , Olho/crescimento & desenvolvimento , Olho/patologia , Hemorragia Retiniana/veterinária , Doenças dos Roedores/patologia , Fatores Etários , Animais , Animais Recém-Nascidos , Hemorragia da Coroide/etiologia , Hemorragia da Coroide/patologia , Olho/irrigação sanguínea , Ratos , Ratos Long-Evans , Ratos Sprague-Dawley , Ratos Wistar , Hemorragia Retiniana/etiologia , Hemorragia Retiniana/patologia , Doenças dos Roedores/etiologia , Índice de Gravidade de Doença , Especificidade da Espécie
16.
J Cell Sci ; 126(Pt 22): 5189-97, 2013 Nov 15.
Artigo em Inglês | MEDLINE | ID: mdl-24046448

RESUMO

The correct formation of primary cilia is central to the development and function of nearly all cells and tissues. Cilia grow from the mother centriole by extension of a microtubule core, the axoneme, which is then surrounded with a specialized ciliary membrane that is continuous with the plasma membrane. Intraflagellar transport moves particles along the length of the axoneme to direct assembly of the cilium and is also required for proper cilia function. The microtubule motor, cytoplasmic dynein-2 mediates retrograde transport along the axoneme from the tip to the base; dynein-2 is also required for some aspects of cilia formation. In most cells, the Golgi lies adjacent to the centrioles and key components of the cilia machinery localize to this organelle. Golgi-localized proteins have also been implicated in ciliogenesis and in intraflagellar transport. Here, we show that the transmembrane Golgi matrix protein giantin (GOLGB1) is required for ciliogenesis. We show that giantin is not required for the Rab11-Rabin8-Rab8 pathway that has been implicated in the early stages of ciliary membrane formation. Instead we find that suppression of giantin results in mis-localization of WDR34, the intermediate chain of dynein-2. Highly effective depletion of giantin or WDR34 leads to an inability of cells to form primary cilia. Partial depletion of giantin or of WDR34 leads to an increase in cilia length consistent with the concept that giantin acts through dynein-2. Our data implicate giantin in ciliogenesis through control of dynein-2 localization.


Assuntos
Cílios/metabolismo , Dineínas/metabolismo , Complexo de Golgi/metabolismo , Proteínas de Membrana/genética , Proteínas de Transporte/metabolismo , Linhagem Celular , Membrana Celular/metabolismo , Centríolos/genética , Cílios/fisiologia , Dineínas/genética , Complexo de Golgi/genética , Proteínas da Matriz do Complexo de Golgi , Humanos , Proteínas de Membrana/metabolismo , Microtúbulos/genética , Microtúbulos/metabolismo
17.
Vet J ; 193(1): 293-5, 2012 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-22104507

RESUMO

Exercise-induced collapse (EIC) is an autosomal recessive disorder in Labrador retrievers. In this study, an allele-specific PCR was developed to detect the point mutation G767T in exon 6 of canine DNM1, previously shown to be responsible for canine EIC. Of 133 Labrador retrievers tested in Japan, 6 (4.5%) were homozygous (EIC) and 50 (37.6%) were heterozygous (carriers) for the G767T mutation.


Assuntos
Doenças do Cão/genética , Dinamina I/genética , Debilidade Muscular/veterinária , Condicionamento Físico Animal/efeitos adversos , Reação em Cadeia da Polimerase/métodos , Polimorfismo Genético , Animais , Doenças do Cão/fisiopatologia , Cães , Técnicas de Genotipagem/veterinária , Japão , Debilidade Muscular/genética , Debilidade Muscular/fisiopatologia , Linhagem , Mutação Puntual , Reação em Cadeia da Polimerase/veterinária , Polimorfismo de Fragmento de Restrição
18.
Bone ; 49(5): 1027-36, 2011 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-21851869

RESUMO

Homozygous rats (ocd/ocd) of a mutant inbred strain, OCD (osteochondrodysplasia), show osteochondrodysplasia, systemic edema, cleft palate, protruding tongue, disproportionate dwarfism, and lethality immediately after birth. Their epiphyses show decreased levels of glycosaminoglycans and weak staining for extracellular matrix proteins. The epiphyseal chondrocytes have large vesicles and expanded endoplasmic reticulum and Golgi apparatus. These phenotypic features are inherited in an autosomal recessive manner, and the ocd locus responsible for these phenotypes has been mapped close to D11Mgh3 on rat chromosome 11. In the present study, we characterized the embryonic pathogenesis of ocd/ocd rats and identified the mutant gene. Subcutaneous edema in the dorsal portion was found at embryonic day (E) 16.5, and the other anomalies described above were apparent after E18.5 in ocd/ocd. Whole mount immunohistochemistry for Sox9 revealed that mesenchymal condensation was delayed in limb bud in ocd/ocd, and skeletal preparation showed that the progression of whole-body chondrogenesis was delayed in ocd/ocd. Histological and immunohistological analyses of the femur showed that cell proliferations of resting and proliferative zones of growth plate were significantly reduced in ocd/ocd embryos. Fine linkage mapping localized the ocd locus within 84kb of positions 65,584-65,668kb containing a part of Golgb1 gene on chromosome 11. Expression of Golgb1 mRNA was found in limb buds, somite derivatives and calvaria. Sequence analysis identified a 10-bp insertion in exon 13 of the Golgb1 gene in ocd/ocd rats. The Golgb1 gene encodes the COPI vesicle tethering factor, giantin. This insertion mutation causes a frame shift, and introduces a premature termination codon at codon 1082, leading to truncation of the C-terminal two thirds of giantin. By in-gel Western analysis using anti-giantin antibody that recognizes an epitope within 200 aa of the C-terminus, the expression of giantin was not detected in ocd/ocd embryos. As the C-terminal region of giantin is required for localization to the Golgi apparatus, these results strongly suggested that giantin is functionally defective in ocd/ocd rats. Therefore, we concluded that mutation of the Golgb1 gene is responsible for the phenotypic characteristics including osteochondrodysplasia of ocd/ocd, and that giantin plays a pivotal role in multiple aspects of chondrogenesis.


Assuntos
Edema/genética , Proteínas de Membrana/genética , Mutagênese Insercional , Osteocondrodisplasias/genética , Animais , Modelos Animais de Doenças , Proteínas da Matriz do Complexo de Golgi , Imuno-Histoquímica , Hibridização In Situ , Reação em Cadeia da Polimerase , Ratos
19.
J Vet Med Sci ; 73(6): 787-95, 2011 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-21307619

RESUMO

Affected rats of the unilateral urogenital anomalies (UUA) strain show renal agenesis restricted to the left side. To determine whether unilateral renal agenesis is a risk factor for the progression of renal insufficiency, we studied age-related pathophysiological alterations in affected rats. Although body growth and food intake were normal, polydipsia and polyuria with low specific gravity were present at 10 weeks and deteriorated further with age. Blood hemoglobin concentrations were normal, though there was slight erythropenia with increased MCV and MCH. Although hypoalbuminemia, hypercholesterolemia, azotemia, and hypermagnesemia were manifested after age 20 weeks, neither hyperphosphatemia nor hypocalcemia was observed. Plasma Cre and UN concentrations gradually increased with age. Cre clearance was almost normal, whereas fractional UN excretion was consistently lower than normal. Proteinuria increased with age, and albumin was the major leakage protein. In addition to cortical lesions, dilated tubules, cast formation, and interstitial fibrosis were observed in the renal medulla of 50 week-old affected rats. Renal weight was increased 1.7-fold and glomerular number 1.2-fold compared with normal rats. These findings show that the remaining kidney in UUA rats is involved not only in compensatory reactions but experiences pathophysiological alterations associated with progressive renal insufficiency.


Assuntos
Anormalidades Congênitas/fisiopatologia , Glomérulos Renais/fisiopatologia , Fatores Etários , Animais , Peso Corporal/fisiologia , Anormalidades Congênitas/sangue , Anormalidades Congênitas/urina , Modelos Animais de Doenças , Ingestão de Alimentos/fisiologia , Histocitoquímica , Rim/anormalidades , Rim/fisiopatologia , Nefropatias/congênito , Masculino , Tamanho do Órgão/fisiologia , Ratos
20.
J Vet Med Sci ; 73(4): 495-9, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21127392

RESUMO

The petit rat (pet/pet) is a new semi-lethal dwarf mutant with anomalies in the thymus and testes, defects inherited as a single autosomal recessive trait. At birth, these pet/pet rats show low birth weight and extremely small thymuses; at 140 days of age, their thymuses show abnormal involution. In the present study, we examined early postnatal development of hypoplastic pet/pet thymuses. In addition to being hypoplastic at birth, pet/pet thymus growth was almost completely impaired during the early postnatal period. As shown by cellular incorporation of BrdU, the mitotic activity was lower in pet/pet than in normal thymuses, and terminal deoxynucleotidyl transferase dUTP nick end labeling assays showed that apoptosis occurred more often in pet/pet than in normal thymus cells during the first few days after birth. These results indicate that postnatal development of the hypoplastic pet/pet thymus is defective due to the reduced proliferation and increased apoptosis of thymic cells.


Assuntos
Anormalidades Múltiplas/patologia , Nanismo/genética , Timo/anormalidades , Timo/crescimento & desenvolvimento , Anormalidades Múltiplas/genética , Animais , Masculino , Mitose , Ratos , Timo/citologia
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