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1.
J Biol Chem ; 275(1): 5-8, 2000 Jan 07.
Artigo em Inglês | MEDLINE | ID: mdl-10617578

RESUMO

Renin plays a key role in controlling blood pressure through its specific cleavage of angiotensinogen to generate angiotensin I (AI). Although possible existence of the other angiotensin forming enzymes has been discussed to date, its in vivo function remains to be elucidated. To address the contribution of renin, we generated renin knockout mice. Homozygous mutant mice show neither detectable levels of plasma renin activity nor plasma AI, lowered blood pressure 20-30 mm Hg less than normal, increased urine and drinking volume, and altered renal morphology as those observed in angiotensinogen-deficient mice. We recently found the decreased density in granular layer cells of hippocampus and the impaired blood-brain barrier function in angiotensinogen-deficient mice. Surprisingly, however, such brain phenotypes were not observed in renin-deficient mice. Our results demonstrate an indispensable role for renin in the circulating angiotensin generation and in the maintenance of blood pressure, but suggest a dispensable role for renin in the blood-brain barrier function.


Assuntos
Angiotensina I/sangue , Barreira Hematoencefálica/fisiologia , Encéfalo/fisiologia , Fenômenos Fisiológicos Cardiovasculares , Renina/deficiência , Angiotensinogênio/sangue , Animais , Pressão Sanguínea , Homeostase , Homozigoto , Rim/patologia , Camundongos , Camundongos Knockout , Sistema Renina-Angiotensina
2.
J Biol Chem ; 274(49): 34605-12, 1999 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-10574924

RESUMO

We previously identified various upstream and downstream regulatory elements and factors important for hepatic expression of the human angiotensinogen (ANG) gene, the precursor of vasoactive octapeptide angiotensin II. In the present study, to further investigate the molecular mechanism of human ANG transcriptional regulation, we generated transgenic mice carrying the fusion gene composed of the 1. 3-kilobase promoter of the human ANG gene, its downstream enhancer, and the chloramphenicol acetyltransferase reporter gene. Because expression of the chloramphenicol acetyltransferase gene was observed strongly in the liver and weakly in the kidney, we suspected that hepatocyte nuclear factor (HNF) 4 with a tissue expression pattern similar to that of the reporter gene would regulate ANG transcription. In vitro assays indicated that HNF4 bound to the promoter elements and strongly activated the ANG transcription, but that chicken ovalbumin upstream promoter transcription factor (COUP-TF), a transcriptional repressor, dramatically repressed human ANG transcription through the promoter elements and the downstream enhancer core elements. Furthermore, COUP-TF dramatically decreased the human ANG transcription in the mouse liver by the Helios Gene Gun system in vivo. These results suggest that an interplay between HNF4 and COUP-TF could be important in hepatic human ANG transcription.


Assuntos
Angiotensinas/genética , Proteínas de Ligação a DNA/genética , Proteínas de Ligação a DNA/metabolismo , Regulação da Expressão Gênica , Fosfoproteínas/metabolismo , Fatores de Transcrição/genética , Fatores de Transcrição/metabolismo , Angiotensinas/biossíntese , Animais , Sequência de Bases , Fatores de Transcrição de Zíper de Leucina e Hélice-Alça-Hélix Básicos , Sítios de Ligação , Fator I de Transcrição COUP , Núcleo Celular/metabolismo , Cloranfenicol O-Acetiltransferase/metabolismo , Relação Dose-Resposta a Droga , Deleção de Genes , Fator 4 Nuclear de Hepatócito , Humanos , Fígado/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Endogâmicos ICR , Camundongos Transgênicos , Dados de Sequência Molecular , Ligação Proteica , Elementos de Resposta , Transcrição Gênica , Células Tumorais Cultivadas
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