Abstract 308: Nephron Specific Deletion Of Angiotensinogen Modulates Blood Pressure

Abstract

It is unknown if intrarenal generation of angiotensinogen (AGT) is important in blood pressure (BP) regulation. Previous studies showed that proximal tubule-specific overexpression of AGT increases BP, while proximal tubule-specific deletion of AGT using the KAP promoter-Cre transgene did not alter BP. The latter study may not have completely eliminated nephron AGT production; in addition, BP was only assessed on a normal salt diet. To evaluate this issue in greater detail, we developed mice with inducible nephron-wide AGT deletion. Mice were generated which were hemizygous for the Pax8-rtTA and LC-1 transgenes and homozygous for loxP flanked AGT alleles to achieve nephron-specific AGT disruption after doxycycline induction. Adult Pax8-rtTA/LC-1/floxed AGT mice at 3 months of age were treated with doxycycline 2 mg/ml in drinking water for 11 days and studied 4 weeks after treatment. Blood pressure (recorded via telemetry) and metabolic balance studies were determined during 5 days of normal, high and low Na diets. Compared to controls, AGT knockout (KO) mice demonstrated significantly lower systolic, diastolic, and mean BPs on all three diets (N=4 each group). The BP reduction was most evident on a low Na diet (mean BP 107 ± 2 mmHg in controls and 88 ± 13 mmHg in AGT KO). Plasma renin concentration was higher in the AGT KO mice as compared to controls on all three diets. There were no detectable differences in weight, urine volume, urine osmolality or urine Na excretion between the controls and KO mice on all three diets, however due to variability, small differences in these parameters may not have been detected. Taken together, these data suggest that nephron AGT may contribute to BP regulation and this is most evident during low Na intake.