Angiotensin deficient FVB/N mice are normotensive

Abstract

Background and Purpose

All previous rodent models lacking the peptide hormone angiotensin II (Ang II) were hypotensive. A mixed background strain with global deletion of the angiotensinogen gene was backcrossed to the FVB/N background (Agt-KO), a strain preferred for transgenic generation. Surprisingly, the resulting line turned out to be normotensive. Therefore, this study aimed to understand the unique blood pressure regulation of FVB/N mice without angiotensin peptides.

Experimental Approach

Acute and chronic recordings of blood pressure (BP) in freely-moving adult mice were performed to establish baseline BP. The pressure responses to sympatholytic and sympathomimetic as well as a nitric oxide inhibitor and donor compounds were used to quantify the neurogenic tone and endothelial function. The role of the renal nerves on baseline BP maintenance was tested by renal denervation. Finally, further phenotyping was done by gene expression analysis, histology and measurement of metabolites in plasma, urine and tissues.

Key Results

Baseline BP in adult FVB/N Agt-KO was unexpectedly unaltered. As compensatory mechanisms Agt-KO presented an increased sympathetic nerve activity and reduced endothelial nitric oxide production. However, FVB/N Agt-KO exhibited the renal morphological and physiological alterations previously found in mice lacking the production of Ang II including polyuria and hydronephrosis. The hypotensive effect of bilateral renal denervation was blunted in Agt-KO compared to wildtype FVB/N mice.

Conclusion and Implications

We describe a germline Agt-KO line that challenges all previous knowledge on BP regulation in mice with deletion of the classical RAS. This line may represent a model of drug-resistant hypertension because it lacks hypotension.