Abstract 174: Angiotensin Production Specifically Within the Subfornical Organ Induces Polydipsia
Angiotensin (ANG) production within the subfornical organ (SFO) is necessary for polydipsia resulting from elevated RAS activity, yet whether SFO ANG is sufficient to increase fluid intake is unknown. We examined the sufficiency of SFO-ANG to cause polydipsia in a novel double transgenic model. The model consists of 1) synapsin-human renin (sR) specifically expressing human renin in neurons via the synapsin promoter, and 2) a construct expressing dsRED at baseline switched to human angiotensinogen (hAGT) in response to Cre-recombinase. Region-specific expression of ANG in the brain of sRA-Red mice can be induced by injection of an adenovirus encoding Cre-recombinase (AdCre). Inducing expression of hAGT in the SFO by ICV injection of AdCre into sRA-Red mice resulted in a progressive increase in fluid intake reaching a maximum 25-days after injection (sRA-Red: 0.26±0.02; NT: 0.17±0.02 mL/g/day, P<0.001). The increase in total fluid intake of sRA-Red mice elicited by ICV AdCre administration was attenuated by an acute ICV injection of losartan (200 mg: 0.14±0.03 mL/g/day, P<0.001) to a level similar to littermate controls receiving losartan (0.17±0.02 mL/g/day). Polydipsia and hypertension due to elevated brain ANG is known to involve the MAPK pathway through activation of angiotensin type 1 receptor (AT1R). The SFO has anatomically and functionally distinct regions. The core region has been implicated in mediating hypertension, whereas the peripheral region controls drinking behavior. ICV-AdCre-sRA-Red mice exhibited increased numbers of phospho-ERK1/2 (62±15 vs 34±13, P=0.05) and phospho-CREB (85±10 vs 55±8, P<0.05) immuno-positive cells per section in SFO. ERK1/2 phosphorylation showed trends toward increased cells per section within both the periphery (26±7 vs 15±6, P=0.10) and core (21±5 vs 11±4, P=0.05) of the SFO. CREB phosphorylation significantly increased in both the periphery (44±9 vs 21±2, P<0.05) and core (27.4±1.6 vs 21.0±1.8 vs, P<0.05) of the SFO. We conclude that selective production of ANG within the SFO is sufficient to increase fluid intake through central activation of AT1R. We are currently examining arterial pressure and testing if the drinking response occurs through ERK1/2- and CREB-dependent pathways in the SFO.
- © 2013 by American Heart Association, Inc.