title: Local production of angiotensin II in the subfornical organ causes elevated drinking.
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 (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.
authors.affiliation: Department of Internal Medicine, Department of Anatomy and Cell Biology, and Center on Functional Genomics of Hypertension, Roy J. and Lucille A. Carver College of Medicine, University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Koji
authors.initials: K
authors.lastname: Sakai
authors.forename: Khristofor
authors.initials: K
authors.lastname: Agassandian
authors.forename: Satoshi
authors.initials: S
authors.lastname: Morimoto
authors.forename: Puspha
authors.initials: P
authors.lastname: Sinnayah
authors.forename: Martin D
authors.initials: MD
authors.lastname: Cassell
authors.forename: Robin L
authors.initials: RL
authors.lastname: Davisson
authors.forename: Curt D
authors.initials: CD
authors.lastname: Sigmund
mesh_terms: D000804:Angiotensin II / Q000235:genetics / Q000502:physiology*; D000818:Animals; D002552:Cerebral Ventricles / Q000187:drug effects / Q000502:physiology; D004327:Drinking Behavior / Q000502:physiology*; D004573:Electrolytes / Q000378:metabolism; D006706:Homeostasis; D006801:Humans; D007276:Injections, Intraventricular; D019808:Losartan / Q000008:administration & dosage / Q000494:pharmacology; D051379:Mice; D008822:Mice, Transgenic; D009474:Neurons / Q000502:physiology; D011401:Promoter Regions, Genetic; D012083:Renin / Q000235:genetics*; D013356:Subfornical Organ / Q000502:physiology*
chemical_list: D004573:Electrolytes; D000804:Angiotensin II; D012083:Renin; D019808:Losartan