Local production of angiotensin II in the subfornical organ causes elevated drinking. J Clin Invest 2007 Apr;117(4):1088-95
Date
04/04/2007Pubmed ID
17404622Pubmed Central ID
PMC1838949DOI
10.1172/JCI31242Scopus ID
2-s2.0-34147153376 (requires institutional sign-in at Scopus site) 119 CitationsAbstract
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 (hAGT(flox)), so that deletions could be induced with Cre recombinase. We targeted SFO-specific ablation of hAGT(flox) by microinjection of an adenovirus encoding Cre recombinase (AdCre). SRA(flox) 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.
Author List
Sakai K, Agassandian K, Morimoto S, Sinnayah P, Cassell MD, Davisson RL, Sigmund CDAuthor
Curt Sigmund PhD Chair, Professor in the Physiology department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
Angiotensin IIAnimals
Cerebral Ventricles
Drinking Behavior
Electrolytes
Homeostasis
Humans
Injections, Intraventricular
Losartan
Mice
Mice, Transgenic
Neurons
Promoter Regions, Genetic
Renin
Subfornical Organ
