Abstract 27: Deficiency of Angiotensinogen in Liver Markedly Reduces Blood Pressure in Lean and Obese Male C57bl6 Mice

Abstract

Objectives: We demonstrated that adipose tissue is a major source of elevated plasma angiotensin II (AngII) in obese hypertensive mice. The liver is the primary source of systemic angiotensinogen (AGT), the AngII precursor. The purpose of this study was to define the contribution of liver-derived AGT on obesity-hypertension in male C57BL/6 mice. Methods and results: Male Agt fl/fl mice expressing albumin-driven Cre recombinase were bred to female mice to generate littermate control ( Agt fl/fl ) or liver-AGT deficient mice ( Agt Alb ). Mice (n=10-13/group) were fed a low fat (LF, 10% kcal as fat) or HF diet (HF, 60 % kcal as fat) for 16 weeks. At baseline, there were no differences in body weight or systolic blood pressure (SBP) between genotypes. Liver AGT deficiency had no effect on the development of obesity ( Agt fl/fl , 48.0±0.4; Agt Alb , 47.5±0.4 g; P>0.05). HF-fed control mice had increased plasma AGT concentrations compared to LF-fed controls (LF: Agt fl/fl , 2.0 ± 0.3; HF, Agt fl/fl , 3.2 ± 0.3 μg/ml; P< 0.05). Plasma AGT concentrations were markedly reduced in liver AGT-deficient mice fed either diet (LF: Agt Alb , 0.5 ± 0.1; HF: Agt Alb , 0.5 ± 0.1μg/ml; P> 0.05). At 9 weeks, there was no effect of HF feeding on SBP in control mice; however, SBP of Agt Alb mice was significantly decreased compared to controls fed either diet (LF: Agt fl/fl , 105 ± 2; Agt Alb , 90 ± 2; HF: Agt fl/fl , 106 ± 2; Agt Alb , 87 ± 6 mmHg, P genotype < 0.05, P diet >0.05) . At 15 weeks, we implanted carotid artery catheters and radiotelemetry implants into anesthetized mice. HF-fed Agt fl/fl mice exhibited a significant increase in SBP compared to LF-fed controls (LF: Agt fl/fl , 119 ± 4; HF: Agt fl/fl , 139 ± 3 mmHg, P< 0.05). Moreover, SBP was significantly decreased in HF-fed Agt Alb mice compared to HF-fed Agt fl/fl controls (HF: Agt fl/fl , 139 ± 3; HF: Agt Alb , 85 ± 4 mmHg, P< 0.05) Surprisingly, LF-fed Agt Alb mice did not survive surgery for radiotelemetry, potentially resulting from marked reductions in blood pressure. Conclusions: Liver AGT deficiency markedly decreases systemic AGT concentrations and blood pressure in male mice fed a LF or HF diet.