Aims/hypothesisThe glomerular endothelial layer is coated by the endothelial surface layer (ESL), which is suggested to play a role in regulation of the permselectivity of macromolecules. Production of heparanase, a degrading enzyme of the ESL, is induced by reactive oxygen species (ROS). We hypothesised that oxidative stress could cause deterioration of the glomerular ESL by induction of heparanase, resulting in increased glomerular permeability.MethodsMale Zucker fatty (ZF) rats with albuminuria and Zucker lean (ZL) rats were used in this study. Some of the ZF rats were treated with the angiotensin II receptor blocker, irbesartan. We determined the amount of ESL by wheat germ agglutinin staining and heparan sulphate proteoglycan production by western blot analysis. Glomerular hyperfiltration of macromolecules was visualised using in vivo microscopy. We used 2′,7′-dichlorofluorescein diacetate-derived chemiluminescence staining to assess ROS production, and heparanase production and expression were determined by western blot analysis and quantitative real-time polymerase chain reaction respectively.ResultsBy 18 weeks of age, ZF rats had developed albuminuria. The glomerular endothelial cell glycocalyx was significantly decreased in ZF compared with ZL rats. Glomerular filtration and the permeability of macromolecules were increased in ZF, but not in ZL rats. Glomerular ROS and heparanase production were significantly increased in ZF compared with ZL rats. These changes in ZF rats were reversed by irbesartan treatment.Conclusions/interpretationIncreased oxidative stress induces glomerular ESL deterioration in part through increased heparanase levels, resulting in exacerbation of glomerular permselectivity and development of albuminuria.Electronic supplementary materialThe online version of this article (doi:10.1007/s00125-010-1810-0) contains supplementary material, which is available to authorised users.

Lower adiponectin levels in circulation are shown to be associated with endothelial dysfunction, which is a crucial feature in the evolution of atherosclerosis. The aim of our study is to evaluate the effect of anti-tumor necrosis factor (TNF) therapy on adiponectin levels with endothelial function and arterial stiffness. Fifteen Japanese patients with rheumatoid arthritis (RA) received infusions with infliximab (3 mg/kg) at weeks 0, 2, and 6. Serum concentrations of adiponectin, endothelial function, and pulse wave velocity (PWV) were measured before each infusion. Endothelium-dependent vasodilatation and endothelium-independent vasodilatation were evaluated as forearm blood flow response to reactive and nitroglycerin-induced hyperemia using strain-gauge plethysmography. Endothelium-dependent vasodilatation was significantly improved at 2 weeks and 6 weeks by treatment with infliximab. PWV remained unchanged. Anti-TNF therapy significantly increased serum adiponectin levels at 2 weeks and 6 weeks. The adiponectin levels were positively correlated with the endothelium-dependent vasodilatation, and negatively with the disease activity score of 28 joints. Our study shows a short-term efficacy of infliximab on adiponectin levels and endothelial dysfunction of patients with RA, and provides additional evidence to support the regulatory role of TNF-alpha on the expression of adiponectin in vivo.

These data showed that glomerular hyperfiltration started from the early phase of diabetes, accompanied by dilatation of afferent arterioles and glomerular hypertrophy.

Renal sympathetic denervation helps to protect against glomerular sclerosis, possibly by suppressing NAD(P)H oxidase activity, thereby decreasing glomerular reactive oxygen species.

It is important to consider a strategy to halt the development of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Oral adsorbent AST-120 retards deterioration in renal function, reducing indoxyl sulfate (IS) accumulation. The aim of this study was to determine whether AST-120 improves endothelial dysfunction by reducing oxidative/nitrative stress in a rat-CKD model. Subtotally nephrectomized (Nx) rats aged 17 weeks were divided into two groups: control rats and rats orally treated with AST-120. Two weeks after initiation of AST-120, serum and urinary IS levels, renal histological scores and endothelium-dependent vascular responses (EDVRs) in the aorta were investigated. EDVR in 5-h incubation with 250 lg ml À1 IS was also examined in normal rat aortas. Nitrotyrosine content, mRNA expression of p47phox, a nicotinamide adenine dinucleotide phosphate (NADPH) oxidase component, and expression and phosphorylation (serine-1177) of endothelial nitric oxide synthase (eNOS) in the aorta were examined in untreated and treated Nx rats. At the end of treatment, renal function and histological scores were not different in the two groups. AST-120 prevented the elevation of serum IS level in Nx rats, reducing urinary IS excretion, and ameliorated decreased EDVR in Nx rats. Incubation with IS tended to reduce EDVR in normal aortas, albeit insignificantly. AST-120 also suppressed nitrotyrosine accumulation and inhibited p47phox expression in Nx rats. The eNOS expression and phosphorylation were similar in the two groups. In conclusion, AST-120 ameliorated endothelial dysfunction and alleviated oxidative/nitrative stress in the aorta through reduced accumulation of IS, independent of renal function, in a rat CKD model.