| Co-Investigator(Kenkyū-buntansha) |
NOMURA Tatsuji Laboratory Animal Research Center, Director, 所長 (10072399)
FUKAMIZU Akiyoshi University of Tsukuba, Institute of Applied Biochemistry, Associate Prof., 応用生物化学系, 助教授 (60199172)
MIYAZAKI Hitoshi University of Tsukuba, Institute of Applied Biochemistry, Associate Prof., 応用生物化学系, 助教授 (40183636)
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| Research Abstract |
The important research results in this project are summarized in the folowing two sections.
1) Functional analysis of angiotensinogen-knockout mice
Genetically altered mice lacking angiotensinogen (Agt-KO) showed an expected phenotype, such as marked hypotension, but unexpected ones including abnormal kidney morphology, reduced survival rates of newborns, and impaired blood-brain barrier function after cold injury. To examine whether disruption of the angiotensinogen gene is responsible for the observed phenotypes, we generated a line of mice heterozygous for the mouse angiotensinogen gene under the control of a mouse metallothionein-I promoter(MT-Agt) and crossmated transgenic mice with Agt-KO mice. The resulting mic (MT-Agt(+/-)/Agt(-/-) : MT-Agt/KO) produced the plasma level of angiotensin I comparable to that of wild-type mice, and the mutant phenotypes were rescued.
2) New function of angiotensinogen knock-out mice
The morphological analysis in a congenic line of angiotensinogen knock-out mice (Ag-KO) revealed the decreased density in granular layer cells of hippocampus and cerebellum, suggesting neuronal cell of Ag-KO susceptible to apoptotic cell death. This phenomenon was further studied by culture of the hippocampal neurons with decreased concentration of serum. Ag-KO neuronal cells, which showed apoptosis by lower concentration of the serum within several hours, however, survived much longer in the presence of angiotensin II (All) and IV(AIV). This anti-apoptotic action was not interfered by AII receptor antagonists. These results suggest that the renin-angiotensin system could play a critical role in central nervous system, preventing neuronal cells from apoptosis not only by All but also AIV.
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