BackgroundSystemic inflammatory response syndrome is a fatal disease because of multiple organ failure. Acute kidney injury is a serious complication of systemic inflammatory response syndrome and its genesis is still unclear posing a difficulty for an effective treatment. Aldose reductase (AR) inhibitor is recently found to suppress lipopolysaccharide (LPS)-induced cardiac failure and its lethality. We studied the effects of AR inhibitor on LPS-induced acute kidney injury and its mechanism.MethodsMice were injected with LPS and the effects of AR inhibitor (Fidarestat 32 mg/kg) before or after LPS injection were examined for the mortality, severity of renal failure and kidney pathology. Serum concentrations of cytokines (interleukin-1β, interleukin-6, monocyte chemotactic protein-1 and tumor necrosis factor-α) and their mRNA expressions in the lung, liver, spleen and kidney were measured. We also evaluated polyol metabolites in the kidney.ResultsMortality rate within 72 hours was significantly less in LPS-injected mice treated with AR inhibitor both before (29%) and after LPS injection (40%) than untreated mice (90%). LPS-injected mice showed marked increases in blood urea nitrogen, creatinine and cytokines, and AR inhibitor treatment suppressed the changes. LPS-induced acute kidney injury was associated with vacuolar degeneration and apoptosis of renal tubular cells as well as infiltration of neutrophils and macrophages. With improvement of such pathological findings, AR inhibitor treatment suppressed the elevation of cytokine mRNA levels in multiple organs and renal sorbitol accumulation.ConclusionAR inhibitor treatment ameliorated LPS-induced acute kidney injury, resulting in the lowered mortality.

The polyol pathway, a collateral glycolytic process, previously considered to be active in high glucose milieu, has recently been proposed to play a crucial role in ischaemia/reperfusion tissue injury. In this study, we explored the role of the polyol pathway in acute kidney injury (AKI), a life-threatening condition, caused by hindlimb ischaemia, and determined if inhibition of the polyol pathway by aldose reductase (AR) inhibitor is beneficial for this serious disorder. Mice 8 weeks of age rendered hindlimb ischaemic for 3 h by the clipping of major supporting arteries revealed marked muscle necrosis with accumulation of sorbitol and fructose in ischaemic muscles. Serum concentrations of blood urea nitrogen (BUN), creatinine phosphokinase (CPK), creatinine, tumour necrosis factor (TNF)-alpha as well as interleukin (IL)-6 were all elevated in these mice. Treatment with AR inhibitor (ARI) effectively suppressed muscle necrosis and accompanying inflammatory reactions and prevented renal failure. Similar to ARI-treated mice, AR-deficient mice were protected from severe ischaemic limb injury and renal failure, showing only modest muscle necrosis and significant suppression of serum markers of renal failure and inflammation. Thus, these findings suggest that the polyol pathway is implicated in AKI caused by ischaemic limb injury and that AR may be a potential therapeutic target for this condition.

The aim of the present study was to reveal the effect of a xanthine oxidoreductase (XOR) inhibitor, topiroxostat (Top), compared with another inhibitor, febuxostat (Feb), in an adenine-induced renal injury model. We used human liver-type fatty acid-binding protein (L-FABP) chromosomal transgenic mice, and urinary L-FABP, a biomarker of tubulointerstitial damage, was used to evaluate tubulointerstitial damage. Male transgenic mice (n = 24) were fed a 0.2% (wt/wt) adenine-containing diet. Two weeks after the start of this diet, renal dysfunction was confirmed, and the mice were divided into the following four groups: the adenine group was given only the diet containing adenine, and the Feb, high-dose Top (Top-H), and low-dose Top (Top-L) groups were given diets containing Feb (3 mg/kg), Top-H (3 mg/kg), and Top-L (1 mg/kg) in addition to adenine for another 2 wk. After withdrawal of the adenine diet, each medication was continued for 2 wk. Serum creatinine levels, the degree of macrophage infiltration, tubulointerstitial damage, renal fibrosis, urinary 15-F2t-isoprostane levels, and renal XOR activity were significantly attenuated in the kidneys of the Feb, Top-L, and Top-H groups compared with the adenine group. Serum creatinine levels in the Top-L and Top-H groups as well as renal XOR in the Top-H group were significantly lower than those in the Feb group. Urinary excretion of L-FABP in both the Top-H and Top-L groups was significantly lower than in the adenine and Feb groups. In conclusion, Top attenuated renal damage in an adenine-induced renal injury model.

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The aim of present study was to investigate the association between plasma xanthine oxidoreductase activity, which has gained attention as a novel preventive target of cardiovascular disease, and various physiological parameters and was to determine the effects of habitual exercise on plasma xanthine oxidoreductase activity in middle-aged and older women. In the cross-sectional study, we investigated the association between plasma xanthine oxidoreductase activity and various physiological parameters in 94 middle-aged and older women. In the interventional study, subjects (n = 22) were divided into two groups: exercise (n = 12) or the control group (n = 10), whereby we examined the effect of 12-week aerobic exercise training on plasma xanthine oxidoreductase activity in middle-aged and older women. The cross-sectional study demonstrated that plasma xanthine oxidoreductase activity was significantly associated with various physiological parameters, including visceral fat and daily step counts. In the interventional study, the plasma xanthine oxidoreductase activity significantly decreased after the 12-week aerobic exercise training, its changes were inversely associated with the changes in daily step counts. Our results revealed that the plasma xanthine oxidoreductase activity was associated with visceral fat accumulation and lack of exercise, and it was decreased by the aerobic exercise training.

Sepsis is a potentially fatal or life shortening syndrome due to infection induced systemic inflammatory responses. Numerous experimental and clinical studies indicate sex differences in sepsis. The outcome and survival rates from sepsis are better in women than in men. Morbidity due to sepsis is complicated by myopathy, and patients face longterm disability due to muscle atrophy and paralysis called intensive care unit acquired weakness (ICU-AW). Here, we examined the effects of estrogen on the septic inflammatory responses in skeletal muscle. 17β-estradiol (E2) attenuated muscle weakness induced by polymicrobial sepsis in ovariectomized mice. Furthermore, E2 attenuated atrophy, and inflammatory cytokine productions induced by lipopolysaccharide (LPS), an endotoxin in C2C12 myotubes. On the other hand, E2 did not change proteolysis pathways such as LPS induced atrogin-1/MAFbx upregulation and autophagosome formation in C2C12 myotubes. These findings indicate that E2 protects skeletal muscle from septic damage by reducing inflammatory cytokines. According to this study, estrogen should be one of the factors of sex difference in sepsis. Compounds with estrogen-like action may be potential seeds for drugs for ICU-AW treatment.