Intermedin ameliorates vascular and renal injury by inhibition of oxidative stress.
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-beta1 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 proinflammatory mediator pathways.
Hagiwara
Makoto
M
Dept. of Biochemistry and Molecular Biology, Medical Univ. of South Carolina, 173 Ashley Ave., Charleston, SC 29425, USA
Bledsoe
Grant
G
Yang
Zhi-Rong
ZR
Smith
Robert S
RS
Chao
Lee
L
Chao
Julie
J
D053607:Adrenomedullin / Q000502:physiology*; D000818:Animals; D030801:Animals, Genetically Modified; D001011:Aorta / Q000502:physiology / Q000503:physiopathology; D001794:Blood Pressure; D001806:Blood Urea Nitrogen; D002196:Capillaries / Q000473:pathology; D003404:Creatinine / Q000097:blood / Q000378:metabolism; D003900:Desoxycorticosterone; D006801:Humans; D007678:Kidney Glomerulus / Q000473:pathology; D007684:Kidney Tubules / Q000098:blood supply / Q000473:pathology; D008297:Male; D009479:Neuropeptides / Q000502:physiology*; D018384:Oxidative Stress / Q000502:physiology*; D036361:Peptide Hormones / Q000235:genetics / Q000627:therapeutic use; D051381:Rats / Q000235:genetics; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D013481:Superoxides / Q000097:blood; D014162:Transfection
C484330:ADM2 protein, human; C499411:Adm2 protein, rat; D009479:Neuropeptides; D036361:Peptide Hormones; D013481:Superoxides; D053607:Adrenomedullin; D003900:Desoxycorticosterone; D003404:Creatinine