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Local production of angiotensin II in the subfornical organ causes elevated drinking

Sakai, K, Agassandian, K, Morimoto, S, Sinnayah, Puspha, Cassell, M, Davisson, R and Sigmund, C (2007) Local production of angiotensin II in the subfornical organ causes elevated drinking. Journal of Clinical Investigation, 117 (4). pp. 1088-1095. ISSN 0021-9738

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Abstract

The mechanism controlling cell-specific Ang II production in the brain remains unclear despite evidence supporting neuron-specific renin and glial- and neuronal-specific angiotensinogen (AGT) expression. We generated double-transgenic mice expressing human renin (hREN) from a neuron-specific promoter and human AGT (hAGT) from its own promoter (SRA mice) to emulate this expression. SRA mice exhibited an increase in water and salt intake and urinary volume, which were significantly reduced after chronic intracerebroventricular delivery of losartan. Ang II–like immunoreactivity was markedly increased in the subfornical organ (SFO). To further evaluate the physiological importance of de novo Ang II production specifically in the SFO, we utilized a transgenic mouse model expressing a floxed version of hAGT (hAGTflox), so that deletions could be induced with Cre recombinase. We targeted SFO-specific ablation of hAGTflox by microinjection of an adenovirus encoding Cre recombinase (AdCre). SRAflox mice exhibited a marked increase in drinking at baseline and a significant decrease in water intake after administration of AdCre/adenovirus encoding enhanced GFP (AdCre/AdEGFP), but not after administration of AdEGFP alone. This decrease only occurred when Cre recombinase correctly targeted the SFO and correlated with a loss of hAGT and angiotensin peptide immunostaining in the SFO. These data provide strong genetic evidence implicating de novo synthesis of Ang II in the SFO as an integral player in fluid homeostasis.

Item Type: Article
Additional Information:

Online ISSN: 1558-8238

Uncontrolled Keywords: ResPubID22088. angiotensin II, Ang II, human renin, human AGT, SRA mice, subfornical organ
Subjects: Faculty/School/Research Centre/Department > School of Biomedical and Health Sciences
FOR Classification > 1101 Medical Biochemistry and Metabolomics
Depositing User: VUIR
Date Deposited: 03 Apr 2012 02:30
Last Modified: 03 Apr 2012 02:30
URI: http://vuir.vu.edu.au/id/eprint/8043
DOI: https://doi.org/10.1172/JCI31242
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Citations in Scopus: 101 - View on Scopus

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