428. Adrenomedullin Gene Delivery Attenuates Renal Damage and Hypertension in Spontaneous Hypertension Rats

Abstract

Background: Human adrenomedullin (AM) is a potent vasodilating peptide with natriuetic activity originally discovered in human pheochromocytoma. AM has been implicated as an important regulator in the renal and cardiovascular systems. By using a new double stranded adeno-associated virus vector (dsAAV), human AM gene can get more rapid and highly efficient transduction than before. In this study, we employed a somatic gene delivery approach to explore its potential hypotensive and protective roles in spontaneous hypertension rats (SHR). Method: The dsAAV was used to harbor human AM gene (or GFP gene) cDNA, and dsAAV-AM and dsAAV-GFP was administered intravenously to two group (n=8 for each) of male SHR (2 × 1010 p.f.u. /rat) respectively. The caudal arterial pressure was measured using tail cuff device once a week, and 24-hour urine and fasting blood were collected to determine levels urinary trace of albumin (Alb) and AM concentrations every 2 weeks. By inserting a catheter into the left ventricle, the heart rate (HR), the left ventricle systolic pressure (LVP) and the maximal/minimum rate of LVP (±LV dp/dtmax) were measured before animals were sacrificed (16 weeks after gene delivery). The main organs were obtained for histological analysis. Results: The dsAAV-AM delivery significantly decreased blood pressure in SHR (up to 28mmHg), which lasted for all experimental duration, compared with the control group (dsAAV-GFP). Expression of human AM mRNA was detected in the heart, renal and liver after human AM gene delivery. Analysis of blood by enzyme-linked immunosorbent assay (ELISA) displayed stable AM gene expression after gene deliveries until experiments ended in dsAAV-AM group, but AM was undetectable in dsAAV-GFP group. In dsAAV-AM group, the level of Alb was much more higher than the dsAAV-GFP group. After human AM gene delivery, the hemodynamic variables deterioration was prevented, compared with the dsAAV-GFP group. Human AM gene delivery significantly attenuated increases fibrosis in the heart and glomerular sclerosis, tubular injuries and protein casts in the kidney. Conclusions: DsAAV-AM can result in significant decrease of blood pressure in SHR, improve renal function and prevent cardiovascular remodeling due to hypertension. These results suggest that dsAAV-AM may have significance in therapeutic applications for hypertension.