Salt-dependent Blood Pressure in Human Aldosterone Synthase-Transgenic Mice

Huiying Gu,Adam Shatara,Yansheng Du,Jian Wang,Nicole Du,Timothy Zhu,Zhizhong Ma,Mark C Kowala,Xin Yi

doi:10.1038/s41598-017-00461-9

Abstract

Hypertension is one of the most important, preventable causes of premature morbidity and mortality in the developed world. Aldosterone is a major mineralocorticoid hormone that plays a key role in the regulation of blood pressure and is implicated in the pathogenesis of hypertension and heart failure. Aldosterone synthase (AS, cytochrome P450 11B2, cyp11B2) is the sole enzyme responsible for the production of aldosterone in humans. To determine the effects of increased expression of human aldosterone synthase (hAS) on blood pressure (BP), we established transgenic mice carrying the hAS gene (cyp11B2). We showed that hAS overexpression increased levels of aldosterone in hAS+/− mice. On high salt diet (HS), BPs of hAS+/− mice were significantly increased compared with WT mice. Fadrozole (an inhibitor of aldosterone synthase) treatment significantly reduced BPs of hAS+/− mice on HS. This is the first time overexpression of AS in a transgenic mouse line has shown an ability to induce HP. Specifically inhibiting AS activity in these mice is a promising therapy for reducing hypertension. This hAS transgenic mouse model is therefore an ideal animal model for hypertension therapy studies.

Highlights

Hypertension is one of the most important, preventable causes of premature morbidity and mortality in the developed world
Our study demonstrates that overexpression of human aldosterone synthase (hAS) in mice results in significantly higher serum levels of aldosterone and high-salt-induced hypertension
Aldosterone is a major mineralocorticoid hormone that plays a key role in the regulation of electrolyte balance and blood pressure

Summary

Introduction

Hypertension is one of the most important, preventable causes of premature morbidity and mortality in the developed world. To determine the effects of increased expression of human aldosterone synthase (hAS) on blood pressure (BP), we established transgenic mice carrying the hAS gene (cyp11B2). Fadrozole (an inhibitor of aldosterone synthase) treatment significantly reduced BPs of hAS+/− mice on HS This is the first time overexpression of AS in a transgenic mouse line has shown an ability to induce HP. The primary secretagogues that stimulate aldosterone biosynthesis are angiotensin II (AngII), adrenocorticotropic hormone (ACTH), and potassium They all elevate cytoplasmatic calcium levels and promote activation of steroidogenic enzymes including aldosterone synthase (AS or 18-hydroxylase)[3]. It suggests that AS encoded by the CYP11B2 gene may contribute to dysregulation of aldosterone synthesis[4, 5]. The AS transgenic mouse model can aid in the identification of novel gene products that have not yet been identified to play a role in PA and hypertension

Methods

Results

Conclusion