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 Agtfl/fl mice expressing albumin-driven Cre recombinase were bred to female mice to generate littermate control (Agtfl/fl) or liver-AGT deficient mice (AgtAlb). 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 (Agtfl/fl, 48.0±0.4; AgtAlb, 47.5±0.4 g; P>0.05). HF-fed control mice had increased plasma AGT concentrations compared to LF-fed controls (LF: Agtfl/fl, 2.0 ± 0.3; HF, Agtfl/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: AgtAlb, 0.5 ± 0.1; HF: AgtAlb, 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 AgtAlb mice was significantly decreased compared to controls fed either diet (LF: Agtfl/fl, 105 ± 2; AgtAlb, 90 ± 2; HF: Agtfl/fl, 106 ± 2; AgtAlb, 87 ± 6 mmHg, Pgenotype< 0.05, Pdiet>0.05). At 15 weeks, we implanted carotid artery catheters and radiotelemetry implants into anesthetized mice. HF-fed Agtfl/fl mice exhibited a significant increase in SBP compared to LF-fed controls (LF: Agtfl/fl, 119 ± 4; HF: Agtfl/fl, 139 ± 3 mmHg, P< 0.05). Moreover, SBP was significantly decreased in HF-fed AgtAlb mice compared to HF-fed Agtfl/fl controls (HF: Agtfl/fl, 139 ± 3; HF: AgtAlb, 85 ± 4 mmHg, P< 0.05) Surprisingly, LF-fed AgtAlb 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.