Indoxyl sulfate upregulates renal expression of icam-1 via production of ros and activation of nf-κb and p53 in proximal tubular cells

Intercellular adhesion molecule 1 (ICAM-1) plays an important role in adhesion of monocytes/macrophages to injured tubulointerstitial tissue. The present study examined whether indoxyl sulfate, a uremic toxin, regulates renal expression of ICAM-1. The effect of indoxyl sulfate on expression of ICAM-1 was determined using human proximal tubular cells (HK-2 cells) and following animals: (1) Dahl salt-resistant normotensive rats (DN), (2) Dahl salt-resistant normotensive indoxyl sulfate-administered rats (DN+IS), (3) Dahl salt-sensitive hypertensive rats (DH), and (4) Dahl salt-sensitive hypertensive indoxyl sulfate-administered rats (DH+IS). DN+IS, DH, and DH+IS rats showed significantly increased mRNA expression of ICAM-1 in the kidneys compared with DN rats. DH+IS rats showed significantly increased mRNA expression of ICAM-1 in the kidneys compared with DH rats. Indoxyl sulfate upregulated mRNA expression of ICAM-1 in HK-2 cells. Inhibitors of NADPH oxidase, NF-κB and p53 suppressed indoxyl sulfate-induced mRNA expression of ICAM-1 in HK-2 cells.In conclusion, indoxyl sulfate upregulates renal expression of ICAM-1 through production of ROS and activation of NF-κB and p53 in proximal tubular cells. Thus, accumulation of indoxyl sulfate in chronic kidney disease might be involved in the pathogenesis of tubulointerstitial injury through induction of ICAM-1 in the kidneys

Indoxyl sulfate, a uremic toxin, downregulates renal expression of Nrf2 through activation of NF-κB

BACKGROUND: Indoxyl sulfate, a uremic toxin, is accumulated in the serum of chronic kidney disease (CKD) patients, accelerating the progression of CKD. In CKD rat kidney, the expressions of nuclear factor (erythroid-derived 2)-like 2 (Nrf2) and its related genes are downregulated. AST-120, an oral sorbent, reduces serum indoxyl sulfate and slows the progression of CKD. The present study aimed to determine whether indoxyl sulfate downregulates Nrf2 expression in human proximal tubular cells and rat kidneys and whether AST-120 upregulates Nrf2 expression in CKD rat kidneys. METHODS: Effects of indoxyl sulfate on expression of Nrf2 were determined using HK-2 cells as human proximal tubular cells and the following animals: (1) Dahl salt-resistant normotensive rats (DN), (2) Dahl salt-resistant normotensive indoxyl sulfate-administered rats (DN+IS), (3) Dahl salt-sensitive hypertensive rats (DH), and (4) Dahl salt-sensitive hypertensive indoxyl sulfate-administered rats (DH+IS). Further, AST-120 was administered to subtotally nephrectomized CKD rats to determine its effect on the expression of Nrf2. RESULTS: Indoxyl sulfate downregulated Nrf2 expression in HK-2 cells. The indoxyl sulfate-induced downregulation of Nrf2 expression was alleviated by an inhibitor of nuclear factor-κB (NF-κB) (pyrrolidine dithiocarbamate) and small interfering RNA specific to NF-κB p65. DN+IS, DH, and DH+IS rats showed decreased renal expression of Nrf2 and its downstream target genes, heme oxygenase-1 (HO-1) and NAD(P)H:quinone oxidoreductase 1 (NQO1), and increased renal expression of 8-hydroxydeoxyguanosine (8-OHdG), a marker of reactive oxygen species (ROS), compared with DN. Thus, indoxyl sulfate, as well as hypertension, downregulated renal expression of Nrf2 in rats. AST-120 upregulated renal expression of Nrf2, HO-1 and NQO1 and suppressed renal expression of 8-OHdG compared with control CKD rats. CONCLUSIONS: Indoxyl sulfate downregulates renal expression of Nrf2 through activation of NF-κB, followed by downregulation of HO-1 and NQO1 and increased production of ROS. Further, AST-120 upregulates renal expression of Nrf2 in CKD rats by removing serum indoxyl sulfate, followed by upregulation of HO-1 and NQO1 and decreased production of ROS

Antenatal antiarrhythmic treatment for fetal tachyarrhythmias: a study protocol for a prospective multicentre trial

Introduction Several retrospective or single-centrestudies demonstrated the efficacy of transplacentaltreatment of fetal tachyarrhythmias. Our retrospectivenationwide survey showed that the fetal therapy willbe successful at an overall rate of 90%. For fetuseswith hydrops, the treatment success rate will be 80%.However, standard protocol has not been established.The objective of this study is to evaluate the efficacy andsafety of the protocol-defined transplacental treatment offetal tachyarrhythmias. Participant recruitment began inOctober 2010.Methods and analysis The current study is a multicentre,single-arm interventional study. A total of 50 fetuseswill be enrolled from 15 Japanese institutions. Theprotocol-defined transplacental treatment is performed forsingletons with sustained fetal tachyarrhythmia ≥180 bpm,with a diagnosis of supraventricular tachycardia or atrialflutter. Digoxin, sotalol, flecainide or a combination is usedfor transplacental treatment. The primary endpoint isdisappearance of fetal tachyarrhythmias. The secondaryendpoints are fetal death related to tachyarrhythmia,proportion of preterm birth, rate of caesarean sectionattributable to fetal arrhythmia, improvement in fetalhydrops, neonatal arrhythmia, neonatal central nervoussystem disorders and neonatal survival. Maternal, fetal andneonatal adverse events are evaluated at 1 month afterbirth. Growth and development are also evaluated at 18and 36 months of corrected age.Ethics and dissemination The Institutional Review Boardof the National Cerebral and Cardiovascular Center ofJapan has approved this study. Our findings will be widelydisseminated through conference presentations and peerreviewedpublications

Functional Single-Walled Carbon Nanotubes and Nanoengineered Networks for Organic- and Perovskite-Solar-Cell Applications.

Carbon nanotubes have a variety of remarkable electronic and mechanical properties that, in principle, lend them to promising optoelectronic applications. However, the field has been plagued by heterogeneity in the distributions of synthesized tubes and uncontrolled bundling, both of which have prevented nanotubes from reaching their full potential. Here, a variety of recently demonstrated solution-processing avenues is presented, which may combat these challenges through manipulation of nanoscale structures. Recent advances in polymer-wrapping of single-walled carbon nanotubes (SWNTs) are shown, along with how the resulting nanostructures can selectively disperse tubes while also exploiting the favorable properties of the polymer, such as light-harvesting ability. New methods to controllably form nanoengineered SWNT networks with controlled nanotube placement are discussed. These nanoengineered networks decrease bundling, lower the percolation threshold, and enable a strong enhancement in charge conductivity compared to random networks, making them potentially attractive for optoelectronic applications. Finally, SWNT applications, to date, in organic and perovskite photovoltaics are reviewed, and insights as to how the aforementioned recent advancements can lead to improved device performance provided