Akira Imaizumi

β2-Adrenoceptor Activation Attenuates Endotoxin-Induced Acute Renal Failure

ABSTRACT. Abnormalities in the β 2 -adrenergic control of organ function have been implicated in the pathogenesis of several disease states, such as septic shock. The objectives of the present study were to define the contribution of β 2 -adrenoceptors (β 2 -AR) to normal renal physiology and to investigate whether overexpression of renal β 2 -AR might be potentially beneficial in preventing progressive renal damage associated with endotoxemia. Adenoviral transgenes containing the human β 2 -AR (Adeno-β 2 -AR) were constructed and delivered into the rat kidney by means of intraparenchymal injections. Administration of 10 9 total viral particles of Adeno-β 2 -AR induced an approximately threefold increase in β 2 -AR density in the renal tissue, which 2 wk after delivery, enhanced GFR and sodium reabsorption compared with control rats. The enhanced GFR was abolished by the addition of the β 2 -AR antagonist, ICI 118,551. Administration of lipopolysaccharide (LPS) caused a reduction in GFR, β 2 -AR density, and cAMP together with enhanced TNF-α mRNA in the kidney. In rats overexpressing β 2 -AR, the reduction in baseline GFR and elevation of TNF-α mRNA and leukocyte infiltration into the kidney associated with the endotoxin were blocked. These findings suggested the possibility that a renal-specific overexpression of β 2 -AR preserves basal renal function in response to a ligand-independent β 2 -AR activation and that the delivery of Adeno-β 2 -AR gene is a potential novel therapeutic strategy for treatment of acute renal failure associated with sepsis.

Renal Effects of β2-Adrenoceptor Agonist and the Clinical Analysis in Children

The objectives of the present study were to define the contribution of β2-adrenoceptors(β2-ARs) agonists to renal physiology and to investigate whether over-expression of renal β2-ARs might be implicated in the pathogenesis of renal dysfunction in children as an adverse effect of β2-AR activation. The renal functional responses to the systemic injection of the β2-AR agonist terbutaline in Wistar rats over-expressing renal β2-AR were compared with those of nontreated rats. Furthermore, we evaluated intrarenal β2-AR expression in 34 children (age 2–15 y) and the changes in serum creatinine levels of 99 children (age 1–15 y) who received β2-AR agonists. The animal study showed that the suppression of glomerular function by terbutaline was associated with a reduction in systemic blood pressure and over-expression of renal β2-ARs. Moreover, in rats over-expressing renal β2-ARs, administration of terbutaline resulted in a high mortality rate after a lipopolysaccharide challenge. The clinical study showed that renal β2-AR expression gradually increased with age and was up-regulated by steroid therapy. These findings indicate that the renal dysfunction caused by β2-AR agonists can be explained, at least partly, by enhanced β2-AR expression in the kidney. This may have important implications for the use of β2-AR agonists in the treatment of sick children with, for example, steroid therapy or endotoxemia.

Adenoviral delivery of the β2-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.