Human Adrenomedullin Gene Delivery Protects Against Cardiac Hypertrophy, Fibrosis and Renal Damage in Hypertensive Dahl Salt-Sensitive Rats
Adrenomedullin (AM) is a potent vasodilator expressed in tissues relevant to cardiac and renal functions. Our previous study showed that delivery of the human AM gene in the form of naked DNA caused a prolonged reduction of blood pressure in genetically hypertensive rats. In this study, we evaluated potential protective effects of adenovirus-mediated AM gene delivery in salt-induced cardiorenal lesions in hypertensive Dahl salt-sensitive (DSS) rats. Adenovirus carrying the human AM cDNA under the control of cytomegalovirus promoter/enhancer (Ad.CMV-hAM) was generated by homologous recombination. Expression of recombinant human AM was detected in the media of HEK 293A cells transfected with Ad.CMV-hAM. A single intravenous injection of Ad.CMV-hAM caused a significant reduction of systolic blood pressure for 4 weeks in DSS rats compared to control rats with or without injection of adenovirus carrying the green fluorescent protein gene. AM gene delivery significantly reduced left ventricular mass, urinary protein, and increased cAMP levels, as well as enhanced renal function as evidenced by increases in glomerular filtration rate and renal blood flow. Morphological investigations showed that AM gene transfer reduced cardiomyocyte diameter and interstitial fibrosis in the heart as well as reduced glomerular sclerosis, tubular disruption and protein cast accumulation in the kidney. Expression of human AM mRNA was identified in rat heart, kidney, lung, liver and aorta, and immunoreactive human AM levels was measured in rat plasma and urine. These results indicate that human AM gene delivery protects against salt-induced hypertension, cardiac and renal lesions in DSS rats via activation of cAMP as a second messenger. These findings provide new insights into the role of AM in salt-induced hypertension and may have implications in therapeutic applications to salt-related cardiovascular and renal diseases.