Intermedin (IMD) is a newly discovered peptide related to calcitonin gene-related peptide and adrenomedullin, and has been shown to reduce blood pressure and reactive oxygen species formation in vivo. In this study, we determined whether IMD exerts vascular and renal protection in DOCA-salt hypertensive rats by intravenous injection of adenovirus harboring the human IMD gene. Expression of human IMD was detected in the rat kidney via immunohistochemistry. IMD administration significantly lowered blood pressure, increased urine volume and restored creatinine clearance. IMD also dramatically decreased superoxide formation and media thickness in the aorta. Vascular injury in the kidney was reduced by IMD gene delivery as evidenced by the prevention of glomerular and peritubular capillary loss. Moreover, IMD lessened morphological damage of the renal tubulointerstitium and reduced glomerular injury and hypertrophy. Attenuation of inflammatory cell accumulation in the kidney by IMD was accompanied by inhibition of p38MAPK activation and intercellular adhesion molecule-1 expression. In addition, IMD gene transfer resulted in a marked decline in myofibroblast and collagen accumulation in association with decreased transforming growth factor-1 levels. Furthermore, IMD increased nitric oxide excretion in the urine and lowered the amount of lipid peroxidation. These results demonstrate that IMD is a powerful renal protective agent with pleiotropic effects by preventing endothelial cell loss, kidney damage, inflammation and fibrosis in hypertensive DOCA-salt rats via inhibition of oxidative stress and pro-inflammatory mediator pathways.