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Mitochondrial oxidative damage is a basic mechanism of aging, and multiple studies demonstrate that this process is attenuated by calorie restriction (CR). However, the molecular mechanism that underlies the beneficial effect of CR on mitochondrial dysfunction is unclear. Here, we investigated in mice the mechanisms underlying CR-mediated protection against hypoxia in aged kidney, with a special focus on the role of the NAD-dependent deacetylase sirtuin 1 (Sirt1), which is linked to CR-related longevity in model organisms, on mitochondrial autophagy. Adult-onset and long-term CR in mice promoted increased Sirt1 expression in aged kidney and attenuated hypoxia-associated mitochondrial and renal damage by enhancing BCL2/adenovirus E1B 19-kDa interacting protein 3-dependent (Bnip3-dependent) autophagy. Culture of primary renal proximal tubular cells (PTCs) in serum from CR mice promoted Sirt1-mediated forkhead box O3 (Foxo3) deacetylation. This activity was essential for expression of Bnip3 and p27Kip1 and for subsequent autophagy and cell survival of PTCs under hypoxia. Furthermore, the kidneys of aged [Sirt1.sup.±] mice were resistant to CR-mediated improvement in the accumulation of damaged mitochondria under hypoxia. These data highlight the role of the Sirt1-Foxo3 axis in cellular adaptation to hypoxia, delineate a molecular mechanism of the CR-mediated antiaging effect, and could potentially direct the design of new therapies for age- and hypoxia-related tissue damage., Introduction Increasing age causes progressive postmaturational deterioration of tissues and organs, leading to impairment of tissue functioning, increased vulnerability to challenges, and death. The kidney is a typical target organ [...]

Metabolic syndrome has been reported to be associated with chronic kidney disease, but the mechanisms remain unclear. Although feeding of a high-fat diet (HFD) to C57BL/6 mice is reported to induce systemic metabolic abnormalities and subsequent renal injuries, such as albuminuria, similar to human metabolic syndrome, alterations in HFD-induced renal injuries have not been fully elucidated in detail. We therefore investigated the structural and functional changes in the kidneys of C57BL/6 mice on a HFD. Six-week-old mice were fed a low-fat diet (LFD; 10% of total calories from fat) or a HFD (60% fat) for 12 wk. Mice fed a HFD showed significant increases in body weight, systolic blood pressure, plasma insulin, glucose, and triglycerides compared with those on a LFD. Accompanying these systemic changes, mice on a HFD showed albuminuria, an increase in glomerular tuft area, and mesangial expansion. These systemic and renal alterations in mice on a HFD were prevented by body weight control with the dietary restriction of feeding a HFD. Furthermore, mice on a HFD showed renal patho-physiological alterations including renal lipid accumulation, an increased accumulation of type IV collagen in glomeruli, an increase in macrophage infiltration in the renal medulla, an increase in urinary 8-hydroxy-2'-deoxyguanosine excretion, and impaired sodium handling. In conclusion, this study suggests that local metabolic alterations in the kidney play important roles in the development of renal injury associated with metabolic syndrome in addition to systemic metabolic changes and an increase in body weight. metabolic syndrome; dietary restriction; lipotoxicity; inflammation; salt-sensitive hypertension

Retinal neovascularization is a major cause of blindness and requires the activities of several signaling pathways and multiple cytokines. Activation of protein kinase C (PKC) enhances the angiogenic process and is involved in the signaling of vascular endothelial growth factor (VEGF). We have demonstrated a dramatic increase in the angiogenic response to oxygen-induced retinal ischemia in transgenic mice overexpressing PKC[beta]2 isoform and a significant decrease in retinal neovascularization in PKC[beta] isoform null mice. The mitogenic action of VEGF, a potent hypoxia-induced angiogenic factor, was increased by 2-fold in retinal endothelial cells by the overexpression of PKC[beta]1 or [beta]2 isoforms and inhibited significantly by the overexpression of a dominant-negative PKC[beta]2 isoform but not by the expression of PKC [alpha], [delta], and [zeta] isoforms. Association of PKC[beta]32 isoform with retinoblastoma protein was discovered in retinal endothelial cells, and PKC[beta]2 isoform increased retinoblastoma phosphorylation under basal and VEGF-stimulated conditions. The potential functional consequences of PKC[beta]-induced retinoblastoma phosphorylation could include enhanced E2 promoter binding factor transcriptional activity and increased VEGF-induced endothelial cell proliferation.

Glycated albumin ( GA) is considered a more reliable marker than glycated hemoglobin ( HbA1c) for monitoring glycemic control, particularly in diabetic hemodialysis patients. We investigated the associations of GA, HbA1c, and random serum glucose levels with survival, and evaluated possible targets for improving survival in diabetic hemodialysis patients. In this prospective, longitudinal, observational study, we enrolled 90 diabetic hemodialysis patients across six dialysis centers in Japan. The median duration of follow-up was 36.0 months (mean follow-up, 29.8 months; range, 3-36 months). There were 11 deaths during the observation period. GA was a significant predictor for mortality (hazard ratio, 1.143 per 1% increase in GA; 95% confidence interval, 1.011-1.292; P = 0.033), whereas HbA1c and random glucose levels were not predictors for mortality. Receiver operating characteristics curve analysis showed that the cutoff value of GA for predicting the risk of mortality was 25%. In the Kaplan- Meier analysis, the cumulative survival rate was significantly greater in patients with GA ≤25% than in patients with GA >25%. GA predicted the risk of all-cause and cardiovascular mortality in diabetic hemodialysis patients. Our results suggest that GA ≤25% is an appropriate target for improving survival in diabetic hemodialysis patients. [ABSTRACT FROM AUTHOR]

Prevention of cardiovascular disease (CVD) is an important therapeutic object of diabetes care. This study assessed whether an index based on plasma free amino acid (PFAA) profiles could predict the onset of CVD in diabetic patients. The baseline concentrations of 31 PFAAs were measured with high-performance liquid chromatography-electrospray ionization-mass spectrometry in 385 Japanese patients with type 2 diabetes registered in 2001 for our prospective observational follow-up study. During 10 years of follow-up, 63 patients developed cardiovascular composite endpoints (myocardial infarction, angina pectoris, worsening of heart failure and stroke). Using the PFAA profiles and clinical information, an index (CVD-AI) consisting of six amino acids to predict the onset of any endpoints was retrospectively constructed. CVD-AI levels were significantly higher in patients who did than did not develop CVD. The area under the receiver-operator characteristic curve of CVD-AI (0.72 [95% confidence interval (CI): 0.64–0.79]) showed equal or slightly better discriminatory capacity than urinary albumin excretion rate (0.69 [95% CI: 0.62–0.77]) on predicting endpoints. A multivariate Cox proportional hazards regression analysis showed that the high level of CVD-AI was identified as an independent risk factor for CVD (adjusted hazard ratio: 2.86 [95% CI: 1.57–5.19]). This predictive effect of CVD-AI was observed even in patients with normoalbuminuria, as well as those with albuminuria. In conclusion, these results suggest that CVD-AI based on PFAA profiles is useful for identifying diabetic patients at risk for CVD regardless of the degree of albuminuria, or for improving the discriminative capability by combining it with albuminuria. [ABSTRACT FROM AUTHOR]

BackgroundKnowledge regarding the association between dietary sodium intake and the incidence of masked hypertension is limited.MethodsA total of 193 Japanese type 2 diabetic outpatients who had been treated with antihypertensive agents and with office blood pressures <140/90 mm Hg were recruited. Masked hypertension was defined as having office blood pressure <140/90 mm Hg and 24-h mean ambulatory blood pressure ≥130/80 mm Hg. The dietary sodium intake was estimated by measuring the 24-h urinary sodium excretion.ResultsMasked hypertension was found in 128 (66.3%) patients. An age- and sex-adjusted univariate logistic regression analysis showed that urinary albumin excretion, renin-angiotensin system inhibitor use, office systolic blood pressure, and amount of dietary sodium intake were significantly associated with masked hypertension. A multivariate logistic regression analysis also identified an older age, renin-angiotensin system inhibitor use, an office elevated systolic blood pressure, and high dietary sodium intake to be independently associated with masked hypertension. When compared with those who consumed a low salt diet (sodium <120 mEq/day), the odds ratio for the risk of exhibiting masked hypertension in patients who consumed a medium salt diet (sodium 120 to <200 mEq/day) or a high salt diet (sodium ≥200 mEq/day) were 5.3 (P < 0.001) and 12.6 (P < 0.001), respectively.ConclusionsMasked hypertension is a common feature in type 2 diabetic patients being treated for hypertension. The observed association with sodium intake raised the hypothesis that excessive sodium intake may play a part in the genesis of masked hypertension in these patients.American Journal of Hypertension 2012; doi:10.1038/ajh.2012.102 [ABSTRACT FROM AUTHOR]

Abstract: Fructose induces several kinds of human metabolic disorders; however, information regarding fructose-induced kidney injury is still limited. This study examined fructose-induced kidney injury in mice and clarified the differential susceptibility of three mouse strains: C57Bl/6J, CBA/JN and DBA/2N. In this study all mice were fed with an equal calorie count for sixteen weeks to remove the influence of total energy intake from metabolic effects by fructose-feeding. Only DBA/2N mice, but not C57Bl/6J and CBA/JN mice, fed with fructose displayed tubulointerstitial fibrosis localized on the outer cortex of the kidney together with the increase of mRNA expression of Kim1 and Ngal in the absence of distinct glomerular lesions and albuminuria – decidedly different from diabetic nephropathy. In time-course study of DBA/2N mice fed with fructose diet, the inflammation and fibrosis in the outer cortex of the kidney were enhancing after eight weeks, in parallel with the accumulation of oxidative stress. This progression of renal damage in DBA/2N mice was accompanied with increasing mRNA expression of GLUT5. These results suggest that the responsiveness of GLUT5 expression to fructose at the kidney is one of pivotal roles for the progression of fructose-induced kidney injury. [Copyright &y& Elsevier]

In hemodialysis (HD) patients the glycated hemoglobin (HbA1c) level may underestimate glycemic control. The aim of this study is to estimate accurate glycemic control in type 2 diabetic patients on HD. Type 2 diabetes patients ( N = 87) who had been receiving maintenance HD for at least one year were enrolled. HbA1c and the percentage of glycated albumin relative to total the serum albumin (%GA) were measured in blood samples and the factors that affected the %GA/HbA1c ratio were examined. There were significant and positive correlations between the plasma glucose and either the HbA1c levels (r = 0.539, P < 0.01) or the %GA level (r = 0.520, P < 0.01). No relationship between the serum albumin levels and %GA levels was observed. A weekly dose of erythropoietin (EPO) was positively correlated with the ratio of %GA/HbA1c and hematocrit (Ht) correlated negatively. There was no significant correlation between the %GA/HbA1c level and the EPO dose in patients with Ht ≥ 30%, although a significant correlation was found between those parameters in the Ht < 30% group. The mean of the %GA/HbA1c ratios in patients with Ht ≥ 30%, with Ht < 30% and treated with EPO < 100 IU/kg/week, and with Ht < 30% and treated with EPO ≥ 100 IU/kg/week were 3.41, 3.56 and 4.13, respectively. In HD patients, accurate glycemic control may be estimated as: HbA1c × 1.14 if Ht ≥ 30%; HbA1c × 1.19 if Ht < 30% and treated with low dosages of EPO; and HbA1c × 1.38 if Ht < 30% and treated with high dosages of EPO. [ABSTRACT FROM AUTHOR]

Renal hypertrophy and deposition of extracellular matrix proteins are consistent findings in diabetic nephropathy and these processes can be halted or reversed by euglycemic control. Using DNA microarray analysis of glomerular RNA from control and diabetic rats we found that the expression levels of insulin-like growth factor 1 receptor (IGF-1R) were increased while those of suppressor of cytokine signaling 2 (SOCS2) and STAT5 were decreased. All of these changes were normalized by islet cell transplantation. Overexpression of SOCS2 in rat mesangial cells inhibited IGF-1-induced activation of extracellular signal-regulated kinase, which subsequently reduced type IV collagen and DNA synthesis, an effect due to interaction of SOCS2 with IGF-1R. Inhibition of SOCS2 overexpression by small interfering RNA suppressed IGF-1R-mediated actions by preventing phosphorylation of tyrosine 317 in the p66Shc adaptor protein; however, overexpression of either SOCS1 or SOCS3 did not affect IGF-1R signaling. Insulin directly increased STAT5 and SOCS2 expression in mesangial cells. This study shows that insulin can inhibit the mitogenic action of IGF-1 in mesangial cells by regulating STAT5/SOCS2 expression. Insulin deficiency may contribute to the mesangial expansion found in diabetes through reduced STAT5/SOCS2 expression.Kidney International (2008) 74, 1434–1443; doi:10.1038/ki.2008.403; published online 13 August 2008 [ABSTRACT FROM AUTHOR]

We examined whether the use of non-steroidal anti-inflammatory drugs (NSAIDs) can affect the anemia and iron status of hemodialysis patients. We recruited patients from six dialysis centers who had undergone maintenance hemodialysis for at least four months. We examined the use of NSAIDs during the past three months based on their medical records and assigned the patients to three groups (group A, non-NSAID group; group B, aspirin group; and group C, non-aspirin NSAID group). Of the 446 patients, 95 (21.3%) were treated with aspirin and 103 (23.1%) were treated with non-aspirin NSAIDs. The serum iron level and transferrin saturation (TSAT) were significantly lower in group C patients than those in group A. However, the ratio of the patients who were administrated iron preparations during the past three months was significantly higher than that in the other two groups. The incidences of positive fecal occult blood tests did not differ substantially between the three groups. The ratios of the patients who were administrated recombinant human erythropoietin were the same between three groups. Using a multiple regression analysis, the administration of non-aspirin NSAIDs was identified as an independent factor for the decreased serum iron and the decreased TSAT levels. A multiple logistic regression analysis revealed that the patients using non-aspirin NSAIDs had an increased the requirement for iron preparation therapy (OR 2.03, 95% CI, 1.28-3.22). The use of non-aspirin NSAIDs may therefore increase the risk of the iron deficiency in patients undergoing hemodialysis. [ABSTRACT FROM AUTHOR]