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NDT Advance Access published online on November 3, 2009
Nephrology Dialysis Transplantation, doi:10.1093/ndt/gfp561
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© The Author 2009. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org


Protection from sepsis-induced acute renal failure by adenoviral-mediated gene transfer of β2-adrenoceptor{dagger}

Akio Nakamura, Ryo Niimi and Yukishige Yanagawa

Department of Pediatrics, Teikyo University School of Medicine, Tokyo, 173, Japan

Correspondence and offprint requests to: Akio Nakamura; E-mail: akio{at}med.teikyo-u.ac.jp



  Abstract

Background. Sepsis is a common cause of acute renal failure (ARF) and results in a high mortality rate. The objective of the present study was to evaluate adenoviral transgenes containing the human β2-adrenoceptor (adeno-β2-AR) as a possible therapy for subjects at high risk for developing sepsis-induced ARF.

Methods. An endotoxaemic rat model of ARF was induced by renal artery occlusion plus subcutaneous injections of Escherichia coli in 4-week-old Wistar rats. A subset of rats was given intraperitoneal injection of the adeno-β2-AR gene.

Results. Sepsis produced a depression in glomerular filtration rate and in the renal β2-AR signalling system, which were both reversed by delivery of the β2-AR gene. While delivery of the adeno-β2-AR gene had no effect on recovery of cytokines and C-reactive protein in the systemic circulation, it did significantly depress (P < 0.01) the expression of the renal cannabinoid-1 (CB-1) receptor, CD14, toll-like receptor 4 (TLR4) and tumour necrosis factor (TNF)-{alpha} protein. Gene delivery also increased nitric oxide (NO) and decreased angiotensin II (Ang II). Finally, transfer of the β2-AR gene also improved the survival of the rats exposed to sepsis-induced ARF.

Conclusions. A renal-specific over-expression of β2-AR, resulting from gene delivery, appeared to modulate renal dysfunction and inflammation following sepsis by altering cAMP–PKA, CB-1 and CD14–TLR4–TNF-{alpha} pathways. In addition, gene delivery and activation of β2-AR produced modulation of systemic NO and Ang II, which further protected against renal dysfunction. Administration of the Adeno-β2-AR gene has potential as a therapeutic agent against ARF following the onset of sepsis.

Keywords: acute renal failure; adenovirus; gene therapy; sepsis; TNF-{alpha}

{dagger} Financial support: For this study, financial support was from a Grant-in-Aid for Scientific Research from the Ministry of Education, Sports, Science and Technology, Japan (17590845) and Kawano Masanori Memorial Foundation for Promotion of Pediatrics.

Received for publication: 2. 2.09
Accepted in revised form: 28. 9.09


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