ABSTRACT-The present study was designed to clarify the role of angiotensin II (Ang II) in modulating renal tumor necrosis factor (TNF)-a and interleukin-6 (IL-6) production and to investigate the effect of one dose of Ang II inhibitor on cytokines production following lipopolysaccharide (LPS) to cause endotoxemia. Two studies were performed: 1) Ang II was infused intravenously at a rate of 0.2 mg/kg per minute for 4 h in rats and then kidneys were collected to assay TNF-a and IL-6 mRNA levels; 2) Four-week-old Wistar rats pre-treated with angiotensin-converting enzyme inhibitor, enalapril, or type I Ang II-receptor antagonist, TCV-116, were injected with LPS (0.1, 0.5, 1.0 mg, i.p.), and then 2 or 4 h later, kidneys were collected to assay TNF-a, IL-6, renin and angiotensinogen mRNA levels. After a 4-h intravenous infusion of Ang II, renal TNF-a or IL-6 mRNA level significantly increased 1.9-fold or 2.1-fold (each P<0.05) to the control level, respectively. LPS stimulated TNF-a, IL-6 and angiotensinogen mRNA levels in the kidney but in rats given enalapril or TCV-116, LPS-induced IL-6 and TNF-a mRNA levels were completely suppressed (each P<0.05). This suggests that a single dose of renin-angiotensin system inhibitor suppressed renal IL-6 and TNF-a production and may prevent cytokine-induced renal damage during endotoxemia.

We present two cases of a 12-year-old Japanese boy and a 14-year-old Japanese girl who had exercise-induced acute renal failure (ARF). They experienced general fatigue, nausea/vomiting, and vague discomfort in the abdomen after physical exercise at school. In case of the boy, abdominal pain subsided, but renal dysfunction lasted 17 days, with peak levels of creatinine 9.4 mg/dl and uric acid 11.3 mg/dl. On the other hand, as the girl had suffered from hypouricemia before, she followed a doctor's guidance on prevention of ARF. Consequently, she was promptly diagnosed as having exercise-induced ARF associated with hypouricemia, and rapidly recovered from ARF within a week. The difference between their clinical courses suggested a possibility that previous laboratory evaluation of serum uric acid assisted in the management of exercise-induced ARF associated with hypouricemia. School-aged children, especially Japanese and Asian, may be advised to have their serum uric acid measured before starting physical training at school.

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ABSTRACT:The objectives of the present study were to define the contribution of ␤ 2 -adrenoceptors(␤ 2 -ARs) agonists to renal physiology and to investigate whether over-expression of renal ␤ 2 -ARs might be implicated in the pathogenesis of renal dysfunction in children as an adverse effect of ␤ 2 -AR activation. The renal functional responses to the systemic injection of the ␤ 2 -AR agonist terbutaline in Wistar rats over-expressing renal ␤ 2 -AR were compared with those of nontreated rats. Furthermore, we evaluated intrarenal ␤ 2 -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 ␤ 2 -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 ␤ 2 -ARs. Moreover, in rats over-expressing renal ␤ 2 -ARs, administration of terbutaline resulted in a high mortality rate after a lipopolysaccharide challenge. The clinical study showed that renal ␤ 2 -AR expression gradually increased with age and was up-regulated by steroid therapy. These findings indicate that the renal dysfunction caused by ␤ 2 -AR agonists can be explained, at least partly, by enhanced ␤ 2 -AR expression in the kidney. This may have important implications for the use of ␤ 2 -AR agonists in the treatment of sick children with, for example, steroid therapy or endotoxemia. ␤ 2 -adrenoceptor (␤ 2 -AR) agonists are used as standard agents in the treatment of bronchial asthma and chronic bronchitis. The majority of the ␤ 2 -AR agonists is eliminated via the kidneys in an unchanged form and it is likely that the compound will exert pharmacological effects during its passage along the nephron. However, these pharmacological effects have, to our knowledge, not been taken into consideration when using these compounds in clinical practice because the significance of ␤ 2 -ARs in the regulation of renal function remains unclear.Renal ␤ 2 -ARs in the rat are predominantly localized to the renal tubular epithelia and the membranes of smooth muscle cells in the renal vasculature (1). From this morphologic evidence, the possibility arises that ␤ 2 -AR activation may impact on glomerular function and thereby sodium and water handling at different nephron segments. We recently demonstrated that injection into the kidney of an adenoviral construct expressing the human ␤ 2 -AR gene induced a widespread increase in ␤ 2 -AR expression in the renal glomeruli and tubules, which was associated with enhanced glomerular filtration and sodium re-absorption as a consequence of overactivation of renal ␤ 2 -ARs (2). Since the level of ␤ 2 -AR expression will importantly determine the magnitude of ␤ 2 -AR-mediated responses following administration of a ␤ 2 -AR agonist (3), the density of intrarenal ␤ 2 -AR expression may determine the impact of ␤ 2 -AR agonists on renal function. However, there have been no studies evaluating the relationship between intrarenal ␤ 2 -AR expression a...

The aim of this study was to define the contribution of renal beta(2)-adrenoceptor (beta(2)-AR) system to regulation of the lipopolysaccharide (LPS) transport system in the kidney of endotoxin-induced septic rats. Seven-week-old Wistar rats (n = 6/groups) pre-treated with the beta(2)-AR antagonist (ICI118,551: 3.14 microg/kg) or saline were injected with LPS (10 mg/kg i.p.) or saline, and then 24 hours later, renal function, beta(2)-AR signaling proteins, innate immune proteins, and cytokines were assayed. The injection of LPS depressed creatinine clearance rate (Ccr) associated with the reduction of renal Gsalpha and cAMP levels by a single dose of ICI118,551. On the other hand, renal CD14, toll-like receptor 4(TLR4), and tumour necrosis factor (TNF)-alpha protein expressions were significantly increased (P < 0.05) by the combination of LPS and ICI118,551. The reduction of Ccr by LPS plus ICI118,551 suggests a possibility that renal specific up-regulation of the CD14-TLR4-TNF-alpha signaling cascade by beta(2)-AR inhibition might be involved in sepsis-induced ARF.