Associations among global long interspersed nuclear element-1 DNA methylation, metal exposure, and chronic kidney disease.

Long interspersed nuclear element-1 (LINE-1) methylation serves as an indicator of global DNA methylation. This study explored the correlation between LINE-1 methylation and chronic kidney disease (CKD). We also evaluated whether LINE-1 methylation could modify the association between CKD and metal exposure. A total of 213 patients with clinically defined CKD, without hemodialysis and 416 age and sex matched controls were recruited. Levels of LINE-1 methylation, total urinary arsenic, blood lead, blood cadmium, and plasma selenium were assessed. The results reveal a positive association between LINE-1 methylation and CKD, with an odds ratio (OR) of 5.30 (95% confidence interval: 2.81 to 9.99). Total urinary arsenic and blood cadmium concentrations were positively related with LINE-1 methylation. This study was the first to observe that low plasma selenium, high blood cadmium, and high blood lead levels significantly and additively interact with increased LINE-1 methylation to increase the OR of CKD. Additionally, high LINE-1 methylation interacted multiplicatively with low plasma selenium to increase the OR of CKD (p < 0.001). This study highlighted the significant association between LINE-1 hypermethylation and CKD. Furthermore, the results demonstrate that LINE-1 methylation can interact with high blood cadmium or low plasma selenium to affect CKD risk.

Effects of osteoporosis medications on bone fracture in patients with chronic kidney disease.

PURPOSE OF THE STUDY: The risk of bone fracture is high in patients with chronic kidney disease (CKD), and aggressive treatment to reduce fragility fracture risk is the major strategy. However, the outcomes of osteoporosis medications in patients with CKD remain unclear. STUDY DESIGN: Patients with stage 3-5 CKD during 2011-2019 were enrolled. Patients were divided into two groups based on receiving osteoporosis medications (bisphosphonates, raloxifene, teriparatide or denosumab) or not. Two groups were matched at a 1:1 ratio by using propensity scores. The outcomes of interest were bone fractures, cardiovascular (CV) events and all-cause mortality. Cox proportional hazard regression models were applied to identify the risk factors. Additional stratified analyses by cumulative dose, treatment length and menopause condition were performed. RESULTS AND CONCLUSIONS: 67 650 patients were included. After propensity score matching, 1654 patients were included in the study and control group, respectively. The mean age was 70.2±12.4 years, and 32.0% of patients were men. After a mean follow-up of 3.9 years, the incidence rates of bone fracture, CV events and all-cause mortality were 2.0, 1.7 and 6.5 per 1000 person-months, respectively. Multivariate analysis results showed that osteoporosis medications reduced the risk of CV events (HR, 0.35; 95% CI, 0.18 to 0.71; p = 0.004), but did not alleviate the risks of bone fracture (HR, 1.48; 95% CI, 0.73 to 2.98; p = 0.28) and all-cause mortality (HR, 0.93; 95% CI, 0.67 to 1.28; p = 0.65). Stratified analysis showed that bisphosphonates users have most benefits in the reduction of CV events (HR, 0.26; 95% CI, 0.11 to 0.64; p = 0.003). In conclusion, osteoporosis medications did not reduce the risk of bone fractures, or mortality, but improved CV outcomes in patients with CKD.

Chronic Kidney Disease: Interaction of Adiponectin Gene Polymorphisms and Diabetes.

Adiponectin is an adipokine multipeptide hormone with insulin-sensitizing; anti-atherosclerotic; and anti-inflammatory properties. Chronic kidney disease (CKD) may be associated with low adiponectin. The adiponectin gene ADIPOQ is thought to be the only major gene responsible for plasma adiponectin levels; which are associated with diabetes and diabetic nephropathy. The purpose of this study was to investigate the association between ADIPOQ polymorphism and CKD. In addition; the combined effects of ADIPOQ polymorphism and diabetes and levels of total urinary arsenic and blood cadmium on CKD were also explored. This study included 215 CKD patients and 423 age-sex matched controls. The ADIPOQ polymorphisms were determined using the Agena Bioscience Mass ARRAY System. The levels of blood cadmium and urinary arsenic species were measured. The ADIPOQ rs182052 GA/AA genotype had a marginally lower odds ratio (OR) for CKD than the GG genotype. The OR (95% confidence interval; CI) was 16.33 (5.72-46.66) of CKD in subjects carrying the ADIPOQ rs182052 GG genotype and diabetes compared to non-diabetes subjects carrying the ADIPOQ rs182052 GA/AA genotype; the interaction term had p = 0.015; and the synergy index was 6.64 (1.81-24.36) after multivariate adjustment. A significant interaction of diabetes and ADIPOQ rs1501299 risk genotype increased the OR of CKD after multivariate adjustment with a synergy index of 0.31 (0.11-0.86) and a multiplicative interaction with p = 0.001. These results suggest that ADIPOQ rs182052 and rs1501299 risk genotypes may significantly modify the association between diabetes and CKD but not the association between total urinary arsenic and blood cadmium and CKD.

Effects of osteoporosis medications on bone fracture in patients with chronic kidney disease.

PURPOSE OF THE STUDY: The risk of bone fracture is high in patients with chronic kidney disease (CKD), and aggressive treatment to reduce fragility fracture risk is the major strategy. However, the outcomes of osteoporosis medications in patients with CKD remain unclear. STUDY DESIGN: Patients with stage 3-5 CKD during 2011-2019 were enrolled. Patients were divided into two groups based on receiving osteoporosis medications (bisphosphonates, raloxifene, teriparatide or denosumab) or not. Two groups were matched at a 1:1 ratio by using propensity scores. The outcomes of interest were bone fractures, cardiovascular (CV) events and all-cause mortality. Cox proportional hazard regression models were applied to identify the risk factors. Additional stratified analyses by cumulative dose, treatment length and menopause condition were performed. RESULTS AND CONCLUSIONS: 67 650 patients were included. After propensity score matching, 1654 patients were included in the study and control group, respectively. The mean age was 70.2±12.4 years, and 32.0% of patients were men. After a mean follow-up of 3.9 years, the incidence rates of bone fracture, CV events and all-cause mortality were 2.0, 1.7 and 6.5 per 1000 person-months, respectively. Multivariate analysis results showed that osteoporosis medications reduced the risk of CV events (HR, 0.35; 95% CI, 0.18 to 0.71; p = 0.004), but did not alleviate the risks of bone fracture (HR, 1.48; 95% CI, 0.73 to 2.98; p = 0.28) and all-cause mortality (HR, 0.93; 95% CI, 0.67 to 1.28; p = 0.65). Stratified analysis showed that bisphosphonates users have most benefits in the reduction of CV events (HR, 0.26; 95% CI, 0.11 to 0.64; p = 0.003). In conclusion, osteoporosis medications did not reduce the risk of bone fractures, or mortality, but improved CV outcomes in patients with CKD.

Emergent Roles of Circular RNAs in Metabolism and Metabolic Disorders.

Circular RNAs (circRNAs) are an emerging group of long non-coding RNAs (lncRNAs) and have attracted attention again according to the progress in high-throughput sequencing in recent years. circRNAs are genome transcripts produced from pre-messenger (m)RNA regions in a specific process called "back-splicing," which forms covalently closed continuous loops. Due to their lack of a 5' cap and 3' poly-adenylated tails, circRNAs are remarkably more stable than linear RNAs. Functionally, circRNAs can endogenously sponge to microRNAs, interact with RNA-binding proteins (RBPs), or translate themselves. Moreover, circRNAs can be expressed in cell type- or tissue-specific expression patterns. Therefore, they are proposed to play essential roles in fine-tuning our body's homeostasis by regulating transcription and translation processes. Indeed, there has been accumulating emergent evidence showing that dysregulation of circRNAs can lead to metabolic disorders. This study explored the current knowledge of circRNAs that regulate molecular processes associated with glucose and lipid homeostasis and related pathogeneses of metabolic disorders. We also suggest the potential role of circRNAs as disease biomarkers and therapeutic targets.

The modulating effect of dietary protein intake on mortality in long-term hemodialysis patients: A nationwide population-based study.

AIMS OF THE STUDY: A high prevalence of protein-energy wasting and malnutrition among uremic patients is associated with an increase in morbidity and mortality. We aimed to investigate the modulating effect of daily dietary protein intake (DPI) evaluated by normalised protein catabolic rate (nPCR) on mortality in long-term haemodialysis (HD) patient from a nationwide population-based study. METHODS USED TO CONDUCT THE STUDY: By Taiwan Renal Registry Data System between 2005 and 2012, we divided the long-term HD patients into average nPCR < 1.2 and nPCR ≥ 1.2 groups according to the current guideline. The relation of nPCR with three-year all-cause and cardiovascular (CV) mortality were evaluated. The cox regression method for predicted mortality by nPCR was used. RESULTS OF THE STUDY: Among 88 330 HD patients, 58 122 (65.8%) patients were in average nPCR < 1.2 group and 30 208 (34.2%) in average nPCR ≥ 1.2 group. Both all-cause and cardiovascular (CV) mortality risks were increased in nPCR < 1.2 group after adjusting for demographics and laboratories cofactors in our multivariate cox regression model. Patients with nPCR < 1.2 and albumin ≥ 3.7 had a higher adjusted hazard ratio (aHR) for all-cause and CV mortality (1.16 [95% confidence interval (CI): 1.07-1.25, P < .001]; 1.15 [95% CI: 1.02-1.31, P = .03], respectively), compared with the reference group with nPCR ≥ 1.2 and albumin ≥ 3.7. Interestingly, there was no difference in mortality risk between low DPI subgroup (nPCR < 1.2 and Alb < 3.7) and the reference group (nPCR ≥ 1.2 and Alb < 3.7). Further stratification analysis revealed that low DPI subgroup (nPCR < 1.2, Alb ≥ 3.7 and TC ≥ 150) had an increased risk of both all-cause and CV mortality (aHR 1.14 [95% CI: 1.04-1.25, P = .005]; aHR 1.17 [95% CI: 1.02-1.35, P = .026], respectively). CONCLUSIONS DRAWN FROM THE STUDY: Low DPI (as presented by nPCR) independently correlated with all-cause and CV mortality among HD patients. Mortality risks were higher in low DPI patients even with normoalbuminaemia and non-hypocholesterolaemia. Further investigations on the importance of increasing DPI in HD patients is warranted.

Inhibition of miR-155 potentially protects against lipopolysaccharide-induced acute lung injury through the IRF2BP2-NFAT1 pathway.

Sepsis-induced lung injury is a lethal complication with no effective treatment options, affecting millions of people worldwide. Oroxylin A (OroA) is a natural flavonoid with potent anticancer effects, but its modulating effect on inflammation through microRNAs (miRs) is not apparent. In this report, we investigated the target genes of the miR pathway mediated by OroA and assessed the potential for novel treatments of septic lung injury. An miR array screening and quantitative polymerase chain reaction identified that miR-155-5p could be a candidate regulated by OroA. Bioinformatics analysis indicated that interferon regulatory factor-2-binding protein-2 (IRF2BP2) might be a target of miR-155-5p, and this hypothesis was verified through reporter assays. In addition, an immunoprecipitation assay demonstrated that OroA increased the binding activity of IRF2BP2 to the nuclear factor of activated T-cells 1 (NFAT1), causing inducible nitric oxide synthase to cause an inflammatory reaction. Finally, the direct injection of short hairpin RNA (shRNA)-miR-155-5p into the bone marrow of mice ameliorated LPS-induced acute lung injury and inflammation in mice. Our results provide new mechanistic insights into the role of the OroA-induced miR-155-5p-IRF2BP2-NFAT1 axis in sepsis, demonstrating that direct bone marrow injection of lentivirus containing shRNA-155-5p could prove to be a potential future clinical application in alleviating sepsis-induced acute lung injury.

Quantitative determination of human IgA subclasses and their Fc-glycosylation patterns in plasma by using a peptide analogue internal standard and ultra-high-performance liquid chromatography/triple quadrupole mass spectrometry.

RATIONALE: Glycosylation on immunoglobulins is important for the immune function. In this study, we developed and validated a method for the absolute quantification of IgA subclasses and relative quantification of IgA-Fc glycopeptides by using affinity purification and ultrahigh-performance liquid chromatography/tandem mass spectrometry (UHPLC/MS/MS). Only micro-volumes of plasma were required from each sample and we also applied the method to discover IgA and IgA-glycopeptide profiles in patients with chronic kidney diseases and IgA nephropathy. METHODS: Peptide M affinity beads were used to purify IgA, and a cost-effective peptide analogue was added as internal standard. With an efficient on-bead digestion process, purified samples were analyzed by UHPLC/MS/MS in multiple reaction monitoring mode. RESULTS: Correlation coefficients were greater than 0.999 for the IgA1 and IgA2 calibration curves and greater than 0.994 for glycopeptide regression curves. Intraday and interday precisions for IgA1 and IgA2 were <1.6% and <5.1% RSD, respectively. Intraday and interday accuracies ranged from 102.6 to 114.9% and 103.5 to 113.5% for IgA1 and IgA2, respectively. Stabilities of IgA1 and IgA2 at -80°C for 7 to 15 days ranged from 96.0 to 109.4%, respectively. The Pearson's correlation coefficient was 0.916 when comparing the IgA quantification results of the 30 clinical samples by using ELISAs and the developed UHPLC/MS/MS method. Compared with healthy controls, IgA and IgA-glycopeptides showed different profiles in patients with chronic kidney diseases and IgA nephropathy. CONCLUSIONS: The developed method showed good validation results, and the absolute quantification results of IgA correlated with those from ELISA. The pilot application study showed that IgA and IgA-glycopeptides can be potential biomarker candidates for kidney diseases, and more clinical sample applications are worth investigating.

MicroRNAs as Biomarkers and Therapeutic Targets in Inflammation- and Ischemia-Reperfusion-Related Acute Renal Injury.

Acute kidney injury (AKI), caused mainly by ischemia-reperfusion, sepsis, or nephrotoxins (such as contrast medium), is identified by an abrupt decline in kidney function and is associated with high morbidity and mortality. Despite decades of efforts, the pathogenesis of AKI remains poorly understood, and effective therapies are lacking. MicroRNAs (miRNAs) are small noncoding RNAs that regulate gene expression at the posttranscriptional level to control cell differentiation, development, and homeostasis. Additionally, extracellular miRNAs might mediate cell-cell communication during various physiological and pathological processes. Recently, mounting evidence indicates that miRNAs play a role in the pathogenesis of AKI. Moreover, emerging research suggests that because of their remarkable stability in body fluids, microRNAs can potentially serve as novel diagnostic biomarkers of AKI. Of note, our previous finding that miR-494 is rapidly elevated in urine but not in serum provides insight into the ultimate role of urine miRNAs in AKI. Additionally, exosomal miRNAs derived from stem cells, known as the stem cell secretome, might be a potential innovative therapeutic strategy for AKI. This review aims to provide new data obtained in this field of research. It is hoped that new studies on this topic will not only generate new insights into the pathophysiology of urine miRNAs in AKI but also might lead to the precise management of this fatal disease.

Multiplex detection of urinary miRNA biomarkers by transmission surface plasmon resonance.

The clinical assessment of short-stranded nucleic acid biomarkers such as miRNAs could potentially provide useful information for monitoring disease progression, prompting definitive treatment decisions. In the past decade, advancements in biosensing technology have led to a shift towards rapid, real-time and label-free detection systems; as such, surface plasmon resonance (SPR) biosensor-based technology has become of high interest. Here, we developed an automated multiplex transmissive surface plasmon resonance (t-SPR) platform with the use of a capped gold nanoslit integrated microfluidic surface plasmon resonance (SPR) biosensor. The automated platform was custom designed to allow the analysis of spectral measurements using wavelength shift (dλ), intensity (dI) and novel area change (dA) for surface binding reactions. A simple and compact nanostructure based biosensor was fabricated with multiplex real-time detection capabilities. The sensitivity and specificity of the microfluidic device was demonstrated through the use of functionalised AuNPs for target molecule isolation and signal enhancement in combination with probes on the CG nanoslit surface. Our work allows for the multiplex detection of miRNA at femtomolar concentrations in complex media such as urine.

Inadequate dietary energy intake associates with higher prevalence of metabolic syndrome in different groups of hemodialysis patients: a clinical observational study in multiple dialysis centers.

BACKGROUND: Metabolic syndrome (MetS) has been established as a risk for cardiovascular diseases and mortality in hemodialysis patients. Energy intake (EI) is an important nutritional therapy for preventing MetS. We examined the association of self-reported dietary EI with metabolic abnormalities and MetS among hemodialysis patients. METHODS: A cross-sectional study design was carried out from September 2013 to April 2017 in seven hemodialysis centers. Data were collected from 228 hemodialysis patients with acceptable EI report, 20 years old and above, underwent three hemodialysis sessions a week for at least past 3 months. Dietary EI was evaluated by a three-day dietary record, and confirmed by 24-h dietary recall. Body compositions were measured by bioelectrical impedance analysis. Biochemical data were analyzed using standard laboratory tests. The cut-off values of daily EI were 30 kcal/kg, and 35 kcal/kg for age ≥ 60 years and < 60 years, respectively. MetS was defined by the American Association of Clinical Endocrinologists (AACE-MetS), and Harmonizing Metabolic Syndrome (HMetS). Logistic regression models were utilized for examining the association between EI and MetS. Age, gender, physical activity, hemodialysis vintage, Charlson comorbidity index, high sensitive C-reactive protein, and interdialytic weight gains were adjusted in the multivariate analysis. RESULTS: The prevalence of inadequate EI, AACE-MetS, and HMetS were 60.5%, 63.2%, and 53.9%, respectively. Inadequate EI was related to higher proportion of metabolic abnormalities and MetS (p <  0.05). Results of the multivariate analysis shows that inadequate EI was significantly linked with higher prevalence of impaired fasting glucose (OR = 2.42, p <  0.01), overweight/obese (OR = 6.70, p <  0.001), elevated waist circumference (OR = 8.17, p <  0.001), AACE-MetS (OR = 2.26, p <  0.01), and HMetS (OR = 3.52, p <  0.01). In subgroup anslysis, inadequate EI strongly associated with AACE-MetS in groups of non-hypertension (OR = 4.09, p = 0.004), and non-cardiovascular diseases (OR = 2.59, p = 0.012), and with HMetS in all sub-groups of hypertension (OR = 2.59~ 5.33, p <  0.05), diabetic group (OR = 8.33, p = 0.003), and non-cardiovascular diseases (OR = 3.79, p <  0.001). CONCLUSIONS: Inadequate EI and MetS prevalence was high. Energy intake strongly determined MetS in different groups of hemodialysis patients.

Intestinal goblet cell carcinoid presenting with recurrent sterile peritonitis in a patient on peritoneal dialysis: a case report.

BACKGROUND: Goblet cell carcinoid is a rare variant of appendiceal carcinoid with mixed endocrine and exocrine features. The most common symptom and signs are abdominal pain, acute appendicitis and palpable mass. Additionally, abdominal pain is common in patient on peritoneal dialysis, which may confound the diagnosis in such patient. CASE PRESENTATION: We report a 71- years- old woman on peritoneal dialysis that experienced several episodes of abdominal cramping pain and sterile peritonitis. She had one episode of severe pain and underwent an appendectomy for suspicion of appendicitis. Goblet cell carcinoid was diagnosed. She had no further abdominal pain after she received appendectomy. CONCLUSIONS: Malignant dialysate was rarely reported in patient with peritoneal dialysis. However, goblet cell carcinoid can initially present with acute appendicitis, chronic intermittent abdominal pain and mimicking peritonitis. In systemically reviewing the literature, this is the first case report of sterile peritonitis with peritoneal dialysis caused by goblet cell carcinoid.

Different effect of hypercholesterolemia on mortality in hemodialysis patients based on coronary artery disease or myocardial infarction.

BACKGROUND: Studies on the association of total cholesterol (TC) levels and mortality in hemodialysis (HD) patients demonstrated conflicting results. The differenct effect of Hypercholesterolemia on HD patients based on the presence of myocardial infarction (MI) or coronary artery disease (CAD) is unknown. METHODS: We analyzed data from the Taiwan Renal Registry Data System (TWRDS) between 2005 and 2012. Patients were divided into MI/CAD or non-MI/CAD group. The primary outcome was three-year mortality. The association between primary outcome and first year average TC and effect of change in cholesterol level between the first and third year of dialysis were explored. RESULTS: Of 90,795 HD patients, 77,762 (85.6%) patients were assigned to non-MI/CAD group and 13,033 (14.4%) to the MI/CAD group. In the non-MI/CAD subjects, both TC > 250 mg/dL and < 150 mg/dL were associated with increased risk of mortality (adjusted hazard ratio [HR]; 95% confidence interval [CI]: 1.27; 1.17-1.37 and 1.14; 1.11-1.18) compared to the reference (TC: 150-200 mg/dL). In the MI/CAD patients, only TC < 150 mg/dL had increased risk (HR; 95% CI: 1.15; 1.08-1.24). In addition, patients of the non-MI/CAD group with highest level of TC (>250 mg/dL) in both first and third year of dialysis had a 64% increased risk for mortality (HR: 1.64, 95% CI: 1.51-1.80). CONCLUSION: In this nationwide hemodialysis cohort, hypercholesterolemia was associated with increased mortality in HD patients without MI/CAD. Further investigation on primary prevention of CAD with statin is warranted.

Urinary micro-RNA biomarker detection using capped gold nanoslit SPR in a microfluidic chip.

Successful diagnosis and treatment of many diseases depends on the availability of sensitive, reliable and low cost tools for the detection of the biomarkers associated with the diseases. Simple methods that use non-invasive biological samples are especially suitable for the deployment in the clinical environment. In this paper we demonstrate the application of a method that employs a capped gold nanoslit surface plasmon resonance (SPR) sensor and a microfluidic chip for the detection of a urinary nucleic acid biomarker in clinical samples. This method detects low concentrations of the biomarker in a relatively large volume (∼1 mL) of the sample. The method utilizes magnetic nanoparticles (MNPs) for the isolation of target molecules and signal enhancement in conjunction with surface plasmon resonance (SPR) on capped gold nanoslits. The ability of the method to detect urinary miRNA-16-5p in AKI patients was tested and the result was compared with the data obtained with the polymerase chain reaction (PCR). miRNA-16-5p has been found to be a specific and noninvasive biomarker for acute kidney injury (AKI). Our method allows the detection of the biomarker in the urine of AKI patients without amplification and labeling of the target molecules.

Activating transcription factor 3 protects against pressure-overload heart failure via the autophagy molecule Beclin-1 pathway.

Activating transcription factor 3 (ATF3), a cAMP response element-binding protein/ATF family transcription factors member, has been implicated in the cardiovascular and inflammatory system and is rapidly induced by ischemic-reperfusion injuries. We performed transverse aortic banding (TAB) experiments using ATF3 gene-deleted mice (ATF3(-/-)) and wild-type (WT) mice to determine what effect it might have on heart failure induced by pressure overloading. Compared with the WT mice, ATF3(-/-) mice were found by echocardiography to have decreased left ventricular contractility with loss of normal cardiac hypertrophic remodeling. The ATF3(-/-) mice had greater numbers of terminal deoxynucleotidyl transferase-mediated digoxigenin-deoxyuridine nick-end labeling-positive cells and higher levels of activated caspase-3, as well as more apoptosis. Restoration of ATF3 expression in the heart of ATF3(-/-) mice by adenovirus-induced ATF3 treatment significantly improved cardiac contractility after TAB. The results from molecular and biochemical analyses, including chromatin immune-precipitation and in vitro /in vivo promoter assays, showed that ATF3 bound to the ATF/cAMP response element of the Beclin-1 promoter and that ATF3 reduced autophagy via suppression of the Beclin-1-dependent pathway. Furthermore, infusion of tert-butylhydroquinone (tBHQ), a selective ATF3 inducer, increased the expression of ATF3 via the nuclear factor erythroid 2-related transcriptional factor, inhibited TAB-induced cardiac dilatation, and increased left ventricular contractility, thereby rescuing heart failure. Our study identified a new epigenetic regulation mediated by the stress-inducible gene ATF3 on TAB-induced cardiac dysfunction. These findings suggest that the ATF3 activator tBHQ may have therapeutic potential for the treatment of pressure-overload heart failure induced by chronic hypertension or other pressure overload mechanisms.

Exosomal ATF3 RNA attenuates pro-inflammatory gene MCP-1 transcription in renal ischemia-reperfusion.

Transcriptional repressor activating transcription factor 3 (ATF3) is induced by various stress stimuli, including inflammation-induced renal injury. In addition, ATF3 also down-regulates adhesion molecules like intercellular adhesion molecule (ICAM), vascular cell adhesion molecule (VCAM), and monocyte chemotactic protein-1 (MCP-1). However, the relation between up-regulated ATF3 after renal ischemia/reperfusion (I/R) injury and MCP-1 is not completely understood. In this study, we demonstrated that, in renal I/R induced inflammation, induction of adhesion molecules (interleukin-6, P-selectin, E-selectin, ICAM, VCAM, and MCP-1) was higher in ATF3-knockout mice than in wild-type animals. Molecular and biochemical analyses revealed that ATF3 binds to the ATF/CRE sites in the MCP-1 promoter and inhibits the secretion of MCP-1 from renal epithelial cells after I/R injury. Urinary exosome containing ATF3 RNA was 60-fold higher in patients with acute kidney injury than in normal controls, but no difference in total urinary ATF3 RNA levels was found. In addition, in vitro study showed that exosome containing ATF3 RNA derived from epithelial cells also inhibits MCP-1 expression in the epithelial cells and macrophage migration. Furthermore, direct administration of the epithelium-derived exosomal ATF3 RNA attenuates I/R induced kidney injury. Together, our studies reveal a novel regulatory mechanism of MCP-1 expression mediated by the exosomal ATF3 RNA under renal I/R insult and suggest a potential targeted therapy for I/R induced acute kidney injury.

Association between the hemodialysis eating index and risk factors of cardiovascular disease in hemodialysis patients.

OBJECTIVE: In this study, a Hemodialysis Eating Index (HDEI) suitable for hemodialysis (HD) patients in Taiwan was developed based on the dietary recommendations of the U.S. National Kidney Foundation for HD patients and the Taiwanese 2011 Daily Food Guide. The HDEI was used to explore HD-associated cardiovascular disease (CVD) risk factors. METHODS: In this prospective study, 108 HD patients from 2 HD centers in Taiwan were recruited as participants in 2010. All participants were older than 20 years. Patient CVD risk factor and 3-day dietary data were collected, and their HDEI scores were calculated. The HDEI scores comprise 12 food-related factors: the consumption of vegetables, fruits, total grains, whole grains, high-protein foods, high biological values, red and white meat, fish, oils, saturated fatty acids or trans fatty acids, nuts, and the duration of multivitamin use. The scores ranged from 5 to 100, and SAS software version 9.3 was used to perform statistical analyses. A P value less than .05 was considered statistically significant. RESULTS: The HDEI scores and serum albumin (Alb) levels were significantly and positively correlated. The participants were divided into 2 groups on the basis of the median HDEI score of 72.2. Two months after HDEI evaluation, the high-HDEI scoring group exhibited significantly decreased levels of serum total cholesterol and increased hemoglobin (Hb) levels. CONCLUSION: The HDEI can be used to reflect selected nutritional status markers, such as Alb and Hb levels and CVD risk factors, for HD patients. The HDEI can also serve as an eating index for HD patients in Taiwan to facilitate CVD prevention.

Adiponectin ameliorates iron-overload cardiomyopathy through the PPARα-PGC-1-dependent signaling pathway.

Adiponectin is a circulating adipose-derived cytokine that may act as an antioxidative and anti-inflammatory protein. Although adiponectin has been reported to exert cytoprotective effects in acute cardiac diseases, its effects on chronic heart failure are less clear. Therefore, we aimed to investigate whether adiponectin would have a beneficial effect in iron-induced chronic heart failure and to elucidate its regulation in cardiomyocytes. Mice were first treated with iron dextran for 4 weeks to induce iron-overload cardiomyopathy. They exhibited decreased survival with impaired left ventricle contractility and decreased serum adiponectin levels. In vivo cardiac adiponectin gene (ADIPOQ) overexpression with adenoassociated virus (AAV)-ADIPOQ ameliorated cardiac iron deposition and restored cardiac function in iron-overloaded mice. In addition, AAV-ADIPOQ-treated iron-overload mice had lower expression of inflammatory markers, including myeloperoxidase activity, monocyte chemotactic protein-1, tumor necrosis factor-α, interleukin-6, and intercellular adhesion molecule-1, than iron-overloaded mice not treated with AAV-ADIPOQ. Our in vitro study showed that adiponectin induced heme oxygenase-1 (HO-1) expression through the peroxisome proliferator-activated receptor (PPAR)α-HO-1 signaling pathway. Furthermore, the adiponectin-mediated beneficial effects were PPARα-dependent as the adiponectin-mediated attenuation of iron deposition was abolished in PPARα-knockout mice. Finally, PPARα-HO-1 signaling involved PPARα and peroxisome proliferator-activated receptor gamma coactivator-1 (PGC-1) binding and nuclear translocation, and their levels were increased by adiponectin therapy. Together, these findings suggest that adiponectin acts as an anti-inflammatory signaling molecule and induces the expression of HO-1 through the PPARα-PGC-1 complex-dependent pathway in cardiomyocytes, resulting in the attenuation of iron-induced cardiomyopathy. Using adiponectin for adjuvant therapies in iron-overload cardiac dysfunction may be an option in the future.

Thromboxane A2 mediates iron-overload cardiomyopathy in mice through calcineurin-nuclear factor of activated T cells signaling pathway.

BACKGROUND: Recent studies demonstrated that iron overload could enhance the production of arachidonic acid and prostanoid, suggesting a causal connection between these signals and iron-overload cardiomyopathy. However, information regarding the downstream signaling is limited. Because thromboxane A2 (TXA2) and prostacyclin are the 2 major prostanoids in the cardiovascular system, and TXA2 plays a major role in vascular atherosclerosis and has pro-inflammatory characteristics, we intended to elucidate the role of TXA2 in iron-overload cardiomyopathy. METHODS AND RESULTS: A 4-week iron loading protocol was instituted for both TXAS gene-deleted (TXAS(-/-)) mice and wild-type (WT) mice, with less severe cardiac fibrosis and preserved normal left ventricular contraction in the TXAS(-/-) mice. Inflammatory profiles, including MCP-1, TNF-α, IL-6, ICAM-1, and myeloperoxidase activity were also lower in the TXAS(-/-) as compared with WT littermates. TXAS supplement to the iron-injured TXAS(-/-) mice re-aggravated cardiac inflammation. Using a TXA2 analog, U46619, for NFAT reporter luciferase activity on cardiomyoctes, and intraperitonal injection of U46619 into nuclear factor of activated T cells (NFAT)-luciferase transgenic mice demonstrated that U46619 increase NFAT expression, and this expression, as well as TNF-α expression, can be blocked by TXA2 receptor antagonist (SQ29548), NFAT-SiRNA, calcineurin inhibitor, or calcium chelator. Finally, intraperitoneal injection of the TNF-α antibody, infliximab, into iron-injured mice decreased TXAS expression and attenuated cardiac fibrosis. CONCLUSIONS: TXA2 mediates iron-overload cardiomyopathy through the TNF-α-associated calcineurin-NFAT signaling pathway.

MicroRNA-494 reduces ATF3 expression and promotes AKI.

MicroRNA-494 mediates apoptosis and necrosis in several types of cells, but its renal target and potential role in AKI are unknown. Here, we found that microRNA-494 binds to the 3'UTR of activating transcription factor 3 (ATF3) and decreases its transcription. In mice, overexpression of microRNA-494 significantly attenuated the level of ATF3 and induced inflammatory mediators, such as IL-6, monocyte chemotactic protein-1, and P-selectin, after renal ischemia/reperfusion, exacerbating apoptosis and further decreasing renal function. Activation of NF-κB mediated this proinflammatory response. In this ischemia/reperfusion model, urinary levels of microRNA-494 increased significantly before the rise in serum creatinine. In humans, urinary microRNA-494 levels were 60-fold higher in patients with AKI than normal controls. In conclusion, upregulation of microRNA-494 contributes to inflammatory or adhesion molecule-induced kidney injury after ischemia/reperfusion by inhibiting expression of ATF3. Furthermore, microRNA-494 may be a specific and noninvasive biomarker for AKI.