Key result
Selective ablation of the brain-specific isoform of renin (renin-b) in mice caused neurogenic hypertension, increased sympathetic nerve activity, and impaired baroreflex sensitivity.
Why the study?
Does selective deletion of the brain-specific isoform of renin (renin-b) cause neurogenic hypertension in mice?
Does selective deletion of the brain-specific isoform of renin (renin-b) cause neurogenic hypertension in mice?
Selective deletion of brain-specific renin (renin-b) in mice causes neurogenic hypertension by removing tonic inhibition of renin-a, revealing a novel genetic control mechanism for brain RAS activity.
Brain renin-b ablation model in mice leaves open its role in BP regulation; human studies needed before clinical relevance.
The renin-angiotensin system (RAS) in the brain is a critical determinant of blood pressure, but the mechanisms regulating RAS activity in the brain remain unclear. Expression of brain renin (renin-b) occurs from an alternative promoter-first exon. The predicted translation product is a nonsecreted enzymatically active renin whose function is unknown. We generated a unique mouse model by selectively ablating the brain-specific isoform of renin (renin-b) while preserving the expression and function of the classical isoform expressed in the kidney (renin-a). Preservation of renal renin was confirmed by measurements of renin gene expression and immunohistochemistry. Surprisingly, renin-b-deficient mice exhibited hypertension, increased sympathetic nerve activity to the kidney and heart, and impaired baroreflex sensitivity. Whereas these mice displayed decreased circulating RAS activity, there was a paradoxical increase in brain RAS activity. Physiologically, renin-b-deficient mice exhibited an exaggerated depressor response to intracerebroventricular administration of losartan, captopril, or aliskiren. At the molecular level, renin-b-deficient mice exhibited increased expression of angiotensin-II type 1 receptor in the paraventricular nucleus, which correlated with an increased renal sympathetic nerve response to leptin, which was dependent on angiotensin-II type 1 receptor activity. Interestingly, despite an ablation of renin-b expression, expression of renin-a was significantly increased in rostral ventrolateral medulla. These data support a new paradigm for the genetic control of RAS activity in the brain by a coordinated regulation of the renin isoforms, with expression of renin-b tonically inhibiting expression of renin-a under baseline conditions. Impairment of this control mechanism causes neurogenic hypertension.
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Shinohara et al. (2016) studied Neurogenic hypertension. Selective ablation of renin-b was evaluated on Blood pressure, sympathetic nerve activity, and baroreflex sensitivity. Selective ablation of the brain-specific isoform of renin (renin-b) in mice caused neurogenic hypertension, increased sympathetic nerve activity, and impaired baroreflex sensitivity.
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