Deficiency of angiotensinogen in hepatocytes markedly decreases blood pressure in lean and obese male mice

Frederique Yiannikouris, Yu Wang, Robin Shoemaker, Nika Larian, Joel Thompson, Victoria L. English, Richard Charnigo, Wen Su, Ming Gong, Lisa A. Cassis

Research output: Contribution to journalArticlepeer-review

24 Scopus citations

Abstract

We recently demonstrated that adipocyte deficiency of angiotensinogen (AGT) ablated high-fat diet-induced elevations in plasma angiotensin II (Ang II) concentrations and obesity-hypertension in male mice. Hepatocytes are the predominant source of systemic AGT. Therefore, in this study, we defined the contribution of hepatocyte-derived AGT to obesity-induced elevations in plasma AGT concentrations and hypertension. Male Agtfl/fl mice expressing albumin-driven Cre recombinase were bred to female Agtfl/fl mice to generate Agtfl/fl or hepatocyte AGT-deficient male mice (AgtAlb). Mice were fed a low-fat or high-fat diet for 16 weeks. Hepatocyte AGT deficiency had no significant effect on body weight. Plasma AGT concentrations were increased in obese Agtfl/fl mice. Hepatocyte AGT deficiency markedly reduced plasma AGT and Ang II concentrations in lean and obese mice. Moreover, hepatocyte AGT deficiency reduced the content and release of AGT from adipose explants. Systolic blood pressure was markedly decreased in lean (by 18 mm Hg) and obese AgtAlb mice (by 54 mm Hg) compared with Agtfl/fl controls. To define mechanisms, we quantified effects of Ang II on mRNA abundance of megalin, an AGT uptake transporter, in 3T3-L1 adipocytes. Ang II stimulated adipocyte megalin mRNA abundance and decreased media AGT concentrations. These results demonstrate that hepatocytes are the predominant source of systemic AGT in both lean and obese mice. Moreover, reductions in plasma angiotensin concentrations in obese hepatocyte AGT-deficient mice may have limited megalin-dependent uptake of AGT into adipocytes for the production of Ang II in the development of obesity-hypertension.

Original languageEnglish
Pages (from-to)836-842
Number of pages7
JournalHypertension
Volume66
Issue number4
DOIs
StatePublished - Oct 11 2015

Bibliographical note

Publisher Copyright:
© 2015 American Heart Association, Inc.

Keywords

  • angiotensinogen
  • blood pressure
  • liver
  • obesity

ASJC Scopus subject areas

  • Internal Medicine

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