Excessive accumulation of extracellular matrix (ECM) in the kidneys and epithelial-to-mesenchymal transition (EMT) of renal tubular epithelial cells contributes to the renal fibrosis that is associated with diabetic nephropathy. Histone deacetylase (HDAC) determines the acetylation status of histones and thereby controls the regulation of gene expression. This study examined the effect of HDAC inhibition on renal fibrosis induced by diabetes or transforming growth factor (TGF)-beta1 and determined the role of reactive oxygen species (ROS) as mediators of HDAC activation. In streptozotocin (STZ)-induced diabetic kidneys and TGF-beta1-treated normal rat kidney tubular epithelial cells (NRK52-E), we found that trichostatin A, a nonselective HDAC inhibitor, decreased mRNA and protein expressions of ECM components and prevented EMT. Valproic acid and class I-selective HDAC inhibitor SK-7041 also showed similar effects in NRK52-E cells. Among the six HDACs tested (HDAC-1 through -5 and HDAC-8), HDAC-2 activity significantly increased in the kidneys of STZ-induced diabetic rats and db/db mice and TGF-beta1-treated NRK52-E cells. Levels of mRNA expression of fibronectin and alpha-smooth muscle actin were decreased, whereas E-cadherin mRNA was increased when HDAC-2 was knocked down using RNA interference in NRK52-E cells. Interestingly, hydrogen peroxide increased HDAC-2 activity, and the treatment with an antioxidant, N-acetylcysteine, almost completely reduced TGF-beta1-induced activation of HDAC-2. These findings suggest that HDAC-2 plays an important role in the development of ECM accumulation and EMT in diabetic kidney and that ROS mediate TGF-beta1-induced activation of HDAC-2.
Systemic inflammation, as evidenced by elevated inflammatory cytokines, is a feature of advanced renal failure and predicts worse survival. Dialysate IL-6 concentrations associate with variability in peritoneal small solute transport rate (PSTR), which has also been linked to patient survival. Here, we determined the link between systemic and intraperitoneal inflammation with regards to peritoneal membrane function and patient survival as part of the Global Fluid Study, a multinational, multicenter, prospective, combined incident and prevalent cohort study (n=959 patients) with up to 8 years of follow-up. Data collected included patient demographic characteristics, comorbidity, modality, dialysis prescription, and peritoneal membrane function. Dialysate and plasma cytokines were measured by electrochemiluminescence. A total of 426 survival endpoints occurred in 559 incident and 358 prevalent patients from 10 centers in Korea, Canada, and the United Kingdom. On patient entry to the study, systemic and intraperitoneal cytokine networks were dissociated, with evidence of local cytokine production within the peritoneum. After adjustment for multiple covariates, systemic inflammation was associated with age and comorbidity and independently predicted patient survival in both incident and prevalent cohorts. In contrast, intraperitoneal inflammation was the most important determinant of PSTR but did not affect survival. In prevalent patients, the relationship between local inflammation and membrane function persisted but did not account for an increased mortality associated with faster PSTR. These data suggest that systemic and local intraperitoneal inflammation reflect distinct processes and consequences in patients treated with peritoneal dialysis, so their prevention may require different therapeutic approaches; the significance of intraperitoneal inflammation requires further elucidation.
Objective To evaluate the predictive value of a single baseline serum C-reactive protein (sCRP) as a marker of mortality in continuous ambulatory peritoneal dialysis (CAPD) patients. Design A review of prospectively collected data in a 2-year follow-up study. Setting Tertiary medical center. Patients The study included 106 patients who were stable and had been on CAPD for a minimum of 3 months. Main Outcome Measures Patient survival rate was the main outcome measure of this study. Other outcome measures were technique survival rate, peritonitis rate, and hospitalized days. Covariables used in the survival analysis were age, sex, the presence of cardiovascular disease or diabetes mellitus, sCRP, serum albumin, hematocrit, cholesterol, HDL-cholesterol, malnutrition by subjective global assessment (SGA), weekly Kt/V urea, and weekly standardized creatinine clearance (SCCr). Results The 2-year patient survival rate was significantly lower in the increased sCRP group than in the normal sCRP group (66.7% vs 94.1%, p = 0.001), although there was no significant difference in technique failure, peritonitis rate, and hospitalized days between the two groups. By Cox proportional hazards analysis, independent predictors of mortality were: cardiovascular disease (relative risk, RR = 8.96, p < 0.005); increased sCRP level (RR = 1.19, p < 0.05); and high hematocrit (RR = 1.18, p < 0.05). ← Conclusion Serum CRP at enrollment is an independent predictor of 2-year patient survival in CAPD patients.
Diabetic nephropathy is the leading cause of end-stage renal disease worldwide and an independent risk factor for all-cause and cardiovascular mortalities in diabetic patients. New insights into the molecular mechanisms that underlie the development and progression of microvascular complications of diabetes including nephropathy are emerging rapidly from experimental and clinical studies. Chronic hyperglycemia is a major initiator of diabetic microvascular complications. Activation of diacylglycerol (DAG)-protein kinase C (PKC) pathway, enhanced polyol pathway, increased oxidative stress, and overproduction of advanced glycation end products have all been proposed as potential cellular mechanisms by which hyperglycemia induces diabetic vascular complications. The DAG-PKC pathway contributes to vascular function in many ways such as the regulation of endothelial permeability, vasoconstriction, extracellular matrix synthesis/turnover, cell growth, angiogenesis, cytokine activation, and leukocyte adhesion. We will briefly review the current knowledge base regarding the pathogenic role for the activation of DAG-PKC pathway in diabetic nephropathy and other microvascular complications of diabetes. The results from animal studies and key clinical studies investigating specific effects of the PKC isoforms on the renal and other vascular tissues to induce diabetic complications are also reviewed.
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