Cardiovascular and metabolic control by the brain renin-angiotensin system

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  • Shinohara Keisuke
    Department of Cardiovascular Medicine, Faculty of Medical Sciences, Kyushu University

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  • 脳内レニン・アンジオテンシン系による循環・代謝調節

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<p>The renin-angiotensin system (RAS) independently exists in the brain apart from the circulating RAS, and an increase in brain RAS activity causes sympathetic hyperactivity. Renin, the rate-limiting enzyme of RAS, has two distinct isoforms: intracellular renin is the dominant isoform in the brain and transcribed from an alternative promoter-first exon, whereas secreted renin is the classical isoform expressed in the kidney. We generated the intracellular renin knockout mice to investigate the role of brain-specific intracellular renin in cardiovascular and metabolic control. Surprisingly, intracellular renin-deficient mice exhibited hypertension and increased sympathetic nerve activity. Further, intracellular renin-deficient mice gained significantly less weight than control mice when fed high-fat diet. Intracellular renin-deficient mice exhibited increased expression of angiotensin-II type 1 receptor in the paraventricular nucleus and an exaggerated depressor response to intracerebroventricular administration of losartan, captopril, or aliskiren. Interestingly, despite an ablation of intracellular renin, expression of secreted renin was increased in rostral ventrolateral medulla. These data support a new paradigm for the genetic control of brain RAS activity by a coordinated regulation of the renin isoforms, with intracellular renin tonically inhibiting expression of secreted renin under baseline conditions. Impairment of this control mechanism may cause hypertension and resistant to obesity through sympathoexcitation.</p>

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