Molecular biological studies on regulatory systems of the circulation in angiotensinogen gene knockout mice.

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To clarify the role of renin angiotensin system (RAS) in the regulation of circulating system, in vivo and in vitro studies were performed using angiotensinogen gene knockout mice (Atg ィイD1-ィエD1/ィイD2-ィエD2 ) and it's control mice (Atg ィイD1+ィエD1/ィイD2+ィエD2 ).(1) Hormonal and electrochemical changes, evalated in the Atg ィイD1+ィエD1/ィイD2+ィエD2 and Atg ィイD1-ィエD1/ィイD2-ィエD2 mice fed salt restricted or salt loading diets as well as normal salt diet, suggested the essential role of RAS in the blood pressure maintenance as well as water electrolyte homeostasis.(2) In the kidney of Atg ィイD1-ィエD1/ィイD2-ィエD2, we found renal vessel specific changes, such as hyperplasia and/or hypertrophy of vascular smooth muscle cells, multi-layered elastic reduplication in the intima and media of renal vessels, and increasing renin containing cells, suggesting the important role of RAS in the normal differentiation and development of the kidney.(3) Neuronal type of nitric oxide synthase (N-NOS) in the macula densa of Ang ィイD1-ィエD1/ィイD2-ィエD2 mice is upregulated and inversely regulated by salt intake and this enzyme activity is functionally linked to renal renin production.(4) In Atg ィイD1-ィエD1/ィイD2-ィエD2 mice, lack of Ang II may upregulated ATィイD21ィエD2-R through translational and/or posttranslational mechanisms in Atg ィイD1-ィエD1/ィイD2-ィエD2 mice.(5) Studies on stretch-induced MAP kinase activation in Atg ィイD1+ィエD1/ィイD2+ィエD2 cardiac myocytes suggested the importance of cardiac RAS, although Ang II is not indispensable for mechanical stretch-induced activation of MAP kinases in Atg ィイD1-ィエD1/ィイD2-ィエD2 cardiac myocytes. Furthermore we found that cytokine gp 130 may play a role in the stretch-induced MAP kinase activation independently of Ang II in cardiac myocyte.