Atrial Natriuretic Peptide Gene Delivery Attenuates Hypertension, Cardiac Hypertrophy, and Renal Injury in Salt-Sensitive Rats

Abstract

To investigate potential therapeutic effects of atrial natriuretic peptide (ANP) gene delivery on renal and cardiac disorders, adenovirus harboring the human ANP gene (Ad.RSV-cANP) was delivered into Dahl salt-sensitive (DSS) rats on a high-salt diet. A single intravenous injection of the ANP gene caused a significant delay of blood pressure increase 3 days post-injection and the effect lasted for more than 5 weeks. A maximal blood pressure reduction of 32.8 mmHg was observed after ANP gene delivery, as compared with that of control rats injected with Ad.CMV-LacZ. Immunoreactive human ANP can be detected in the heart, lung, and kidney of rats after gene delivery. ANP gene delivery caused significant increases in renal blood flow, glomerular filtration rate, sodium output, urine excretion, and urinary cGMP levels. These beneficial effects were reflected morphologically by a reduction in cardiomyocyte size, attenuation of the glomerular–sclerotic lesions, tubular injury and arterial thickening. This study demonstrated the usefulness of somatic gene transfer as a new tool for ANP gene delivery in studying salt-related hypertension and renal and cardiovascular diseases. In addition, the findings also suggest that ANP gene delivery may have potential in therapeutic applications. Human atrial natriuretic peptide gene delivery in hypertensive Dahl salt-sensitive rats fed a high-salt diet produces sustained reduction of the systolic blood pressure and partial attenuation of cardiac hypertrophy and renal injury. These findings provide new insights into the role of the atrial natriuretic peptide in salt-related hypertension as well as cardiovascular and renal functions and may have significance in future therapeutic applications.