Adenoviral delivery of the beta2-adrenoceptor gene in sepsis: a subcutaneous approach in rat for kidney protection.
Successful gene therapy requires gene delivery that is efficient, has an optimal route of administration and has biosafety. The aims of the present study were to evaluate the safety and applicability of the subcutaneous delivery route for adenoviral transgenes containing the human beta(2)-adrenoceptor (adeno-beta(2)-AR) and to investigate whether this approach prevented renal dysfunction in a rat model of endotoxaemic shock induced by LPS (lipopolysaccharide). Subcutaneous administration of adeno-beta(2)-AR (a total of 10(10) viral particles) significantly increased beta-AR density in the kidney, lung and liver, but was without effect on physiological and plasma biochemical parameters. Moreover, this dose of virus did not cause any of the potential toxic responses of viral administration, such as inflammation and tissue TNF (tumour necrosis factor)-alpha expression. Although the LPS challenge caused a decrease in glomerular filtration rate, fractional excretion of sodium and renal beta-AR density in all groups, the reduction in renal function was significantly less in the rats given adeno-beta(2)-AR compared with non-treated rats. Thus, although further evaluation will be required, this initial study demonstrated that the subcutaneous injection of adeno-beta(2)-AR was efficient, comparatively non-pathogenic and potentially therapeutic to deal with acute renal failure associated with sepsis.
Nakamura
Akio
A
Department of Paediatrics, Teikyo University School of Medicine, Tokyo 173, Japan. akio@med.teikyo-u.ac.jp
Imaizumi
Akira
A
Niimi
Ryo
R
Yanagawa
Yukishige
Y
Kohsaka
Takao
T
Johns
Edward J
EJ
D058186:Acute Kidney Injury / Q000378:metabolism / Q000517:prevention & control* / Q000821:virology; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D015152:Blotting, Northern / Q000379:methods; D005355:Fibrosis; D005818:Genetic Engineering; D015316:Genetic Therapy / Q000379:methods*; D005822:Genetic Vectors / Q000008:administration & dosage*; D007279:Injections, Subcutaneous; D007668:Kidney / Q000276:immunology / Q000378:metabolism / Q000821:virology; D008070:Lipopolysaccharides; D023421:Models, Animal; D012333:RNA, Messenger / Q000032:analysis; D051381:Rats; D017208:Rats, Wistar; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D012449:Safety; D018805:Sepsis / Q000276:immunology / Q000378:metabolism / Q000628:therapy*; D014161:Transduction, Genetic / Q000379:methods; D014409:Tumor Necrosis Factor-alpha / Q000235:genetics
D008070:Lipopolysaccharides; D012333:RNA, Messenger; D018343:Receptors, Adrenergic, beta-2; D014409:Tumor Necrosis Factor-alpha