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Clinical Science (2005) 109, (503–511) (Printed in Great Britain)

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Adenoviral delivery of the b₂-adrenoceptor gene in sepsis: a subcutaneous approach in rat for kidney protection

Akio NAKAMURA*, Akira IMAIZUMI*, Ryo NIIMI*, Yukishige YANAGAWA*, Takao KOHSAKA† and Edward J. JOHNS‡

*Department of Paediatrics, Teikyo University School of Medicine, Tokyo 173, Japan, †Department of Immunology, National Children's Medical Centre, Tokyo 154, Japan, and ‡Department of Physiology, University College Cork, Cork, Ireland

Key words: adenovirus, b₂-adrenoceptor, endotoxaemia, gene delivery, kidney, TNF (tumour necrosis factor).

Abbreviations: AR, adrenoceptor, adeno-b₂-AR, adenoviral constructs containing the human b₂-AR gene; BP, blood pressure; BPI, bactericidal/permeability-increasing protein; BUN, blood urea nitrogen; CPK, creatine phosphokinase; FEK, fractional excretion of potassium; FENa, fractional excretion of sodium; GFR, glomerular filtration rate; GOT, glutamic-oxaloacetic transaminase; GPT, glutamic-pyruvic transaminase; H&E, haematoxylin and eosin; HR, heart rate; IL, interleukin; i.p., intraperitoneally; LDH, lactate dehydrogenase; LPS, lipopolysaccharide; PKA, cAMP-dependent protein kinase; TNF, tumour necrosis factor; t.v.p, total virus particles.

Correspondence: Dr Akio Nakamura (email akio@med.teikyo-u.ac.jp).

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 b₂-adrenoceptor (adeno-b₂-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-b₂-AR (a total of 10¹⁰ viral particles) significantly increased b-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)-a expression. Although the LPS challenge caused a decrease in glomerular filtration rate, fractional excretion of sodium and renal b-AR density in all groups, the reduction in renal function was significantly less in the rats given adeno-b₂-AR compared with non-treated rats. Thus, although further evaluation will be required, this initial study demonstrated that the subcutaneous injection of adeno-b₂-AR was efficient, comparatively non-pathogenic and potentially therapeutic to deal with acute renal failure associated with sepsis.

Received 14 March 2005/27 July 2005; accepted 3 August 2005

Published as Immediate Publication 3 August 2005, doi:10.1042/CS20050088

©2005 The Biochemical Society