Regulation of soluble epoxide hydrolase (sEH) activity by adamantyl alkyl urea-based sEH inhibitor (AUDA) in renal ischemia-reperfusion injury (IRI).

<p>A: Plasma epoxyoctadecenoic acid (EpOME) and dihydroxyoctadec-12-enoic acid (DHOME) levels were quantified to investigate the enzyme activity of sEH. B: 9,10-, 12,13-, and total EpOME plasma concentrations were significantly increased in response to AUDA in renal IRI. C: The EpOME/DHOME ratio was significantly increased (*<i>P</i><0.05 compared to sham+vehicle; #<i>P</i><0.05 compared to sham+AUDA; †<i>P</i><0.05 compared to IRI+vehicle).</p

Effects of 12-(3-adamantan-1-ylureido)-dodecanoic acid (AUDA) on renal expression of soluble epoxide hydrolase (sEH) in ischemia-reperfusion injury (IRI) in kidneys.

<p>A: Histological changes were consistent with the functional changes (×200). IRI induced tubular necrosis, consisting of disruption and sloughing of tubular epithelial cells. Arrows indicate necrotic tubules, and asterisks indicate tubular casts. Tubular injury was increased in disease-control mice compared to AUDA-treated mice. B: Expression was quantified by a renal pathologist in a blinded fashion (*<i>P</i><0.05). Scores ranged from 1–5, based on the percentage of tubules affected (1: <10%; 2: 10–25%; 3: 25–50%; 4: 50–75%; 5: >75%). C: sEH was expressed in the endothelium of intraglomerular capillary loops and peritubular capillaries. D and E: Ischemic injury induced the down-regulation of sEH, but AUDA administration had no effect on sEH expression. DAPI was used as counterstaining. <i>EPHX2,</i> gene encoding sEH.</p

Protective effects of soluble epoxide hydrolase (sEH) inhibitor on hypoxic damage via neovascularization.

<p>A: Hypoxia inducible factor (HIF)-1α, vascular endothelial growth factor (VEGF), VEGF receptor-2 (KDR), and erythropoietin (EPO) were enhanced by 12-(3-adamantan-1-ylureido)-dodecanoic acid (AUDA) administration. (*<i>P</i><0.05 compared to sham; #<i>P</i><0.05 compared to sham; †<i>P</i><0.05 compared to ischemia-reperfusion injury (IRI) +vehicle). B: Hypoxia induced the down-regulation of sEH in human umbilical vein endothelial cells (HUVECs). Cells were incubated with or without AUDA (10 µM) under hypoxic (1% O₂) or normoxic conditions (20% O₂) for 24 h. Apoptosis of HUVECs was assessed by p53 expression. Hypoxia induced apoptosis in HUVECs, but AUDA treatment reduced apoptosis associated with enhancement of HIF-1α. DAPI was used for counterstaining (magnification, ×400). C and D: c-kit (CD117) expression decreased after IRI, but was amplified by AUDA administration (magnification, ×800). E: AUDA treatment significantly enhanced c-kit expression. Data represent the results of one of three independent experiments (<i>n</i> = 6 per group; †<i>P</i><0.05 compared to IRI+vehicle). F: AUDA treatment increased c-kit and KDR expression levels in HUVECs exposed to hypoxia.</p

Early Referral to a Nephrologist Improved Patient Survival: Prospective Cohort Study for End-Stage Renal Disease in Korea

<div><p>The timing of referral to a nephrologist may influence the outcome of chronic kidney disease patients, but its impact has not been evaluated thoroughly. The results of a recent study showing an association between early referral and patient survival are still being debated. A total of 1028 patients newly diagnosed as end-stage renal disease (ESRD) from July 2008 to October 2011 were enrolled. Early referral (ER) was defined as patients meeting with a nephrologist more than a year before dialysis and dialysis education were provided, and all others were considered late referral (LR). The relationship of referral pattern with mortality in ESRD patients was explored using a Cox proportional hazards regression models. Time from referral to dialysis was significantly longer in 599 ER patients than in 429 LR patients (62.3±58.9 versus 2.9±3.4 months, P<0.001). Emergency HD using a temporary vascular catheter was required in 485 (47.2%) out of all patients and in 262 (43.7%) of ER compared with 223 (52.0%) of LR (P = 0.009). After 2 years of follow-up, the survival rate in ER was better than that in LR (hazard ratio [HR] 2.38, 95% confidence interval [CI] 1.27–4.45, P = 0.007). In patients with diabetes nephropathy, patient survival was also significantly higher in ER than in LR (HR 4.74, 95% CI 1.73–13.00, P = 0.002). With increasing age, HR also increased. Timely referral to a nephrologist in the predialytic stage is associated with reduced mortality.</p> </div

Effects of soluble epoxide hydrolase (sEH) inhibitor on the pro-/anti-inflammatory microenvironment in injured kidneys.

<p>A: Proinflammatory cytokines TNF-α and MCP-1 were significantly suppressed, while IL-10 and TGF-β were enhanced by treatment with 12-(3-adamantan-1-ylureido)-dodecanoic acid (AUDA), as shown by real-time PCR. B: The proinflammatory cytokine IL-6 was decreased and the regulatory cytokines IL-4 and IL-10 were augmented by AUDA, as shown by multiplex cytokine assay. (*<i>P</i><0.05 compared to sham; #<i>P</i><0.05 compared to sham; †<i>P</i><0.05 compared to IRI+vehicle). C: AUDA decreased the infiltration of inflammatory cells (macrophages (F4/80), lymphocytes (CD3), and neutrophils (MPO)) mainly trafficked in the interstitial area. D: AUDA attenuated the infiltration of macrophages/monocytes and T cells expressing CD3, as shown by flow cytometry. F4/80, marker for pan-macrophage; CD44, indicative marker for effector-memory T-cells; CD45, leukocyte common antigen; Gr1, myeloid differentiation antigen.</p

Role of soluble epoxide hydrolase (sEH) activity in ischemia-reperfusion injury (IRI) in kidneys.

<p>A: The adamantyl alkyl urea-based sEH inhibitor, 12-(3-adamantan-1-ylureido)-dodecanoic acid (AUDA) reduced IRI in the kidney. All values are given as means±S.E. (<i>n</i> = 6 per group for each experiment). Data represent one of three independent experiments. Day 0, before bilateral IRI; day 1, 24 h after bilateral IRI; day 2, 48 h after bilateral IRI (two-way ANOVA with Bonferroni post-testing; *<i>P</i><0.05; **<i>P</i><0.01; ***<i>P</i><0.001). B: Administration of AUDA had no effect on blood pressure during the procedure.</p

Baseline characteristics of the study subjects.

*<p>Statistical differences between anemia and non-anemia groups are calculated.</p>†<p>Arithmetic mean (standard error).</p>‡<p>Geometric mean (standard error).</p><p>Abbreviations: TIBC, total iron-binding capacity; GFR, glomerular filtration rate.</p

Scatter plot with the lowess regression curve between serum 25-hydroxyvitamin D and hemoglobin levels.

<p>Scatter plot with the lowess regression curve between serum 25-hydroxyvitamin D and hemoglobin levels.</p

Spline curve (solid line) with 95% confidence intervals (two dashed lines) using generalized additive model for Gaussian distribution and process of determining the threshold level for an association using Akaike’s information criterion.

<p>Total subjects (A), males (B), premenopausal females (C), and postmenopausal females (D). AIC, Akaike’s information criterion.</p

Predicted probability of anemia according to the serum 25-hydroxyvitamin D levels.

<p>Total subjects (A), males (B), premenopausal females (C), and postmenopausal females (D). Red and black lines represent predicted probability of anemia and 95% confidence interval, respectively.</p