Protection from sepsis-induced acute renal failure by adenoviral-mediated gene transfer of beta2-adrenoceptor.
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 beta(2)-adrenoceptor (adeno-beta(2)-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-beta(2)-AR gene.


RESULTS
Sepsis produced a depression in glomerular filtration rate and in the renal beta(2)-AR signalling system, which were both reversed by delivery of the beta(2)-AR gene. While delivery of the adeno-beta(2)-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 beta(2)-AR gene also improved the survival of the rats exposed to sepsis-induced ARF.


CONCLUSIONS
A renal-specific over-expression of beta(2)-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 beta(2)-AR produced modulation of systemic NO and Ang II, which further protected against renal dysfunction. Administration of the Adeno-beta(2)-AR gene has potential as a therapeutic agent against ARF following the onset of sepsis.
Nakamura
Akio
A
Department of Pediatrics, Teikyo University School of Medicine, Tokyo 173, Japan. akio@med.teikyo-u.ac.jp
Niimi
Ryo
R
Yanagawa
Yukishige
Y
D058186:Acute Kidney Injury / Q000382:microbiology* / Q000517:prevention & control*; D000256:Adenoviridae / Q000235:genetics*; D000818:Animals; D004195:Disease Models, Animal; D004926:Escherichia coli / Q000472:pathogenicity; D004927:Escherichia coli Infections / Q000150:complications; D015316:Genetic Therapy / Q000379:methods*; D006801:Humans; D007279:Injections, Subcutaneous; D007668:Kidney / Q000378:metabolism / Q000382:microbiology; D018950:Lipopolysaccharide Receptors / Q000378:metabolism; D051381:Rats; D017208:Rats, Wistar; D043884:Receptor, Cannabinoid, CB1 / Q000378:metabolism; D018343:Receptors, Adrenergic, beta-2 / Q000235:genetics*; D012078:Renal Artery Obstruction / Q000150:complications; D018805:Sepsis / Q000150:complications*; D015398:Signal Transduction / Q000502:physiology; D051194:Toll-Like Receptor 1 / Q000378:metabolism; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism
D018950:Lipopolysaccharide Receptors; D043884:Receptor, Cannabinoid, CB1; D018343:Receptors, Adrenergic, beta-2; D051194:Toll-Like Receptor 1; D014409:Tumor Necrosis Factor-alpha