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Neural Control of Blood Pressure Regulation
The mechanism controlling cell-specific Ang-II production in the brain remains unclear despite evidence supporting neuron-specific reninand glial- and neuronal-specific angiotensinogen expression. We generated double transgenic mice (termed SRA) expressing human renin (hREN) rom a neuron-specific promoter and human angiotensinogen (hAGT) from its own promoter to emulate this expression. SRA mice exhibited an increase in water and salt intake and urinary volume which was 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 hAGTflox so deletions could be induced with Cre-recombinase. We targeted SFO- specific ablation of hAGTflox 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 AdCre/AdeGFP, but not after 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. The results of this study published in the Journal of Clinical Investigation (117:1088-1095, 2007) was the topic of an editorial in the journal and illustrates how we use a combination of high tech genetics, genetic techniques and integrative physiology to make fundamental discoveries on the neural control of blood pressure regulation.