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

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)-α 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-α 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.