Adrenomedullin gene delivery attenuates hypertension, cardiac remodeling, and renal injury in deoxycorticosterone acetate-salt hypertensive rats.

Abstract

Adrenomedullin (AM) is a potent vasodilator and natriuretic peptide that plays an important role in cardiorenal function. In this study, we explored the potential protective role of AM in volume-dependent hypertension by somatic gene delivery. Adenovirus containing the human AM cDNA under the control of the cytomegalovirus promoter/enhancer was administered into deoxycorticosterone acetate (DOCA)-salt hypertensive rats via tail vein injection. A single injection of the human AM gene resulted in a prolonged reduction of blood pressure with a maximal reduction of 41 mm Hg 9 days after gene delivery. Human AM gene delivery enhanced renal function, as indicated by a 3-fold increase in renal blood flow and a 2-fold increase in glomerular filtration rate (n=5, P<0.05). Histological examination of the kidney revealed a significant reduction in glomerular sclerosis, tubular injury, luminol protein cast accumulation, and interstitial fibrosis as well as urinary protein. Human AM gene delivery caused significant decreases in left ventricular weight and cardiomyocyte diameter, which were accompanied by reduced interstitial fibrosis and extracellular matrix formation within the heart. Expression of human AM mRNA was detected in the kidney, adrenal gland, heart, aorta, lung, and liver; immunoreactive human AM levels were measured in urine and plasma. Significant increases in urinary and cardiac cAMP levels were observed in DOCA-salt rats receiving the human AM gene, indicating activation of the AM receptor. These findings showed that AM gene delivery attenuates hypertension, protects against cardiac remodeling and renal damage in volume-overload hypertension, and may have significance in therapeutic applications in cardiovascular and renal diseases.