RESUMO
Previously we have shown that bone marrow (BM) transplantation (BMT) can attenuate progression of and even ameliorate mesangial sclerosis (MS) in Wt1-heterozygous mice. However, it is unclear whether BMT performed before the onset of disease will prevent the development of MS. To investigate whether intravenous (i.v.) or intrarenal (i.r.) administration of BM have equal effects on the progression of MS in Wt1-heterozygous mice, young Wt1-heterozygous mice that had not yet developed renal disease were used as recipients for BMT. After preconditioning with 750 cGy radiation, mice were transplanted with one million wild-type BM via i.v. or i.r. administration. All recipients and untreated controls were assessed for urinary albumin loss, renal pathology, and BM donor-derived renal cells over time. Representative kidney samples were subjected to transmission electron microscopy (TEM) analysis. Interestingly, i.r. and i.v. administration of BM cells gave comparable hematopoietic engraftment levels, and both were able to prevent the onset of MS as assessed by improved lifespan, renal function, renal histology, and TEM analysis. Taken together, we show for the first time that MS can be prevented if BMT is performed before disease onset. Similar therapeutic effects were obtained whether the BM was administered i.v. or i.r.
Assuntos
Transplante de Medula Óssea/métodos , Células Mesangiais/patologia , Nefroesclerose/prevenção & controle , Animais , Células da Medula Óssea/metabolismo , Células da Medula Óssea/patologia , Modelos Animais de Doenças , Progressão da Doença , Regulação da Expressão Gênica , Hematopoese , Células Mesangiais/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Mutantes , Modelos Genéticos , Nefroesclerose/genética , Nefroesclerose/patologia , Fatores de Tempo , Condicionamento Pré-Transplante/métodos , Proteínas WT1/genética , Proteínas WT1/metabolismoRESUMO
Alternative splicing of Wt1 results in the insertion or omission of the three amino acids KTS between zinc fingers 3 and 4. In vitro experiments suggest distinct molecular functions for + and -KTS isoforms. We have generated mouse strains in which specific isoforms have been removed. Heterozygous mice with a reduction of +KTS levels develop glomerulosclerosis and represent a model for Frasier syndrome. Homozygous mutants of both strains die after birth due to kidney defects. Strikingly, mice lacking +KTS isoforms show a complete XY sex reversal due to a dramatic reduction of Sry expression levels. Our data demonstrate distinct functions for the two splice variants and place the +KTS variants as important regulators for Sry in the sex determination pathway.
Assuntos
Processamento Alternativo/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Genes do Tumor de Wilms/genética , Néfrons/embriologia , Proteínas Nucleares , Proteínas Repressoras , Processos de Determinação Sexual , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Transporte Ativo do Núcleo Celular , Animais , Animais Recém-Nascidos , Apoptose , Sequência de Bases , Sobrevivência Celular , Receptor Nuclear Órfão DAX-1 , Proteínas de Ligação a DNA/química , Transtornos do Desenvolvimento Sexual , Éxons/genética , Feminino , Glomerulosclerose Segmentar e Focal/genética , Glomerulosclerose Segmentar e Focal/metabolismo , Gônadas/anormalidades , Gônadas/embriologia , Gônadas/metabolismo , Gônadas/patologia , Masculino , Camundongos , Mutagênese/genética , Néfrons/anormalidades , Néfrons/metabolismo , Néfrons/ultraestrutura , Isoformas de Proteínas/química , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Sítios de Splice de RNA/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Receptores do Ácido Retinoico/genética , Proteína da Região Y Determinante do Sexo , Síndrome , Fatores de Transcrição/química , Proteínas WT1RESUMO
Experimens were performed on 36 cats, showing that stimulation of the central end of the left major splanchnic nerve induced an increase of the plasma cortisol level. The centripetal effect was abolished by lesioning the septal nuclei, just as the same as injection of propranolol into the nuclei; but phentolamine had no such preventive action. All the findings show that it is the noradrenergic beta-receptor system of the septal nuclei that exerts a considerable effect on cortisol secretion.
