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Background There is a paucity of epidemiological data regarding pesticide intoxication-associated acute kidney injury (AKI). Therefore, the aim of this study was to identify the epidemiological features, risk factors, and adverse outcomes of AKI in this population. Methods The data used in this multi-center, hospitalized population-based, retrospective study were retrieved from electronic medical records. AKI was defined as an acute increase in serum creatinine according to the criteria of Kidney Disease: Improving Global Outcomes. The Charlson Comorbidity Index was used to evaluate the burden of in-hospital mortality. Results Of 3,371 adult patients in 11 hospitals, 398 (11.8%) were diagnosed with AKI (grade 1, 218 [6.5%]; grade 2, 89 [2.6%]; grade 3, 91 [2.7%]). Herbicide intoxication was associated with the highest incidence of AKI (53.5%) and higher grades of AKI. After multivariable adjustment, pesticide categories and moderate or severe renal disease were independently associated with AKI. As compared with the referred category, insecticide and herbicide intoxications were associated with a 1.3-fold (95% CI 1.688–3.245) and 3.8-fold (95% CI 3.537–6.586) greater risk of AKI. Regardless of the pesticide category, AKI was independently associated with in-hospital mortality, with odds ratios of 3.433 (95% CI 1.436–8.203) for insecticides, 2.153 (95% CI 1.377–3.367) for herbicides, and 4.524 (95% CI 1.230–16.632) for unclassified or other pesticides. Conclusion AKI is common in pesticide intoxication and associated with an increased in-hospital mortality. Herbicides pose the greatest risks of AKI and death.

Aim To develop a model for predicting renal recovery in cardiac surgery patients with acute kidney injury (AKI) requiring renal replacement therapy (RRT). Methods Data from a prospective randomized controlled trial, conducted in a tertiary hospital to compare the survival effect of two dosages of hemofiltration for continuous RRT in cardiac surgery patients between March 20, 2012 and August 9, 2015, were used to develop the model. The outcome was renal recovery defined as alive and dialysis-free 90 days after RRT initiation. Multivariate logistic regression with a stepwise backward selection of variables based on Akaike Information Criterion was applied to develop the model, which was internally validated using bootstrapping. Model discrimination, calibration, and clinical value were assessed using the concordance index (C-Index), calibration plots, and decision curve analysis, respectively. Results Totally, 211 patients with AKI requiring RRT (66.8% male) with median age of 57 years were included. The incidence of renal recovery was 33.2% (n = 70). The model included six variables: body mass index stratification, baseline estimated glomerular filtration rate, hypertension, sepsis, mean arterial pressure, and mechanical ventilation. The C-Index for this model was 0.807 (95%CI, 0.744-0.870). After correction by the bootstrap, the C-Index was 0.780 (95%CI, 0.720-0.845). The calibration plots indicated good consistency between actual observations and model prediction of renal recovery. Decision curve analysis demonstrated the model was clinical usefulness. Conclusion We developed and validated a model to predict the chance of renal recovery in cardiac surgery patients with AKI requiring RRT. This article is protected by copyright. All rights reserved.

A dietary protein intake (DPI) of between 0.6 and 0.8 g protein per kilogram body weight per day (g/kg/day) is frequently recommended for adults with moderate-to-advanced chronic kidney disease (CKD). However, evidence on whether patients with diabetic kidney disease (DKD) actually benefit from a DPI of ≤ 0.8 g/kg/day and from a low-protein diet (LPD) at CKD stages 1–3 has not been consistent. We systematically searched MEDLINE, EMBASE, Cochrane Library, Web of Knowledge, as well as the bibliographies of articles identified in the search, for eligible randomized controlled trials that had investigated the effects of LPD (prescribed DPI

Histone deacetylase 6 (HDAC6) is the specific subtype of HDACs which preferentially located in the cytoplasm, and is crucial in insulin signalling. However, the role of HDAC6 in type 2 diabetic nephropathy (DN) remains undefined. In current study, we observed that HDAC6 was markedly activated in the kidneys of type 2 diabetic patients and db/db mice with albuminuria, along with the advanced glycation end products (AGE)‐treated podocytes. Selective inhibition of HDAC6 activity protected kidneys from hyperglycaemia in db/db mice. Notably, overexpressing HDAC6 inhibited autophagy and promoted motility aside from the apoptosis of podocytes exposed to AGE. We further determined that HDAC6 regulated the autophagy partially by decreasing the acetylation of α‐tubulin at the residue of lysine 40. In contrast, we confirmed that there was no interaction of HDAC6 with α‐tubulin at the sites of lysine 112 and lysine 352. Consistently, inhibiting HDAC6 by siRNA or the selective inhibitor, tubacin, restored the autophagy level and motility of podocytes and rescued podocytes from AGE stimulation. We provide strong evidence of an unexpected role of HDAC6 in the cascade that modulates podocytes autophagy and motility, enlightening that HDAC6 may be a promising therapeutic target for DN treatment.

Intravenous injection of alteplase is recommended for patients with minor disabling and not non-disabling ischemic stroke symptoms within 4.5 h of ischemic stroke symptom onset. However, it is hard for clinicians to distinguish which type of minor ischemic stroke is disabled at an early stage. In this study, we aimed to demonstrate early neutrophil-to-lymphocyte ratio is a prognostic marker in acute minor stroke or transient ischemic attack. 196 patients diagnosed with acute minor stroke or transient ischemic attack within 24 h of symptom onset were enrolled. Patients were divided into three groups according to the neutrophil-to-lymphocyte ratio value ( 3). Clinical, neuroradiological, laboratory and follow-up data were collected from electronic database. Functional outcome was assessed by modified Rankin Scale. Neutrophil-to-lymphocyte ratio associated with functional outcome of 90 days was evaluated by logistic regression analysis, and we used receiver operating characteristic curve analysis to detect the overall predictive accuracy of this marker. Early neutrophil-to-lymphocyte ratio was associated with an increased risk of short-term functional outcome (OR 4.502, 95% CI 1.533–13.046, P = 0.006). The optimal cutoff value of neutrophil-to-lymphocyte ratio for prediction of short-term unfavorable outcome was 2.94 with a sensitivity of 69.6% and a specificity of 77.1% (area under the curve: 0.767, 95% CI 0.691–0.843). Early neutrophil-to-lymphocyte ratio is associated with short-term unfavorable functional outcome in patients with acute minor stroke or transient ischemic attack. Early neutrophil-to-lymphocyte ratio is beneficial for clinicians to distinguish minor disabling ischemic stroke at an early stage.

Posttraumatic stress disorder is a mental disorder with a known cause, yet effective behavioral and pharmacotherapies remain elusive for many afflicted patients. Propranolol is suggested to be effective as a fear-reducing agent when paired with behavioral therapy soon after trauma when psychological stress is high, possibly dampening or preventing the later development of posttraumatic stress disorder. In our previous study, we found propranolol efficaciously reduced fear retention induced by reactivation via β-adrenergic receptors in lateral amygdala. However, it is unclear which subtypes of β-adrenergic receptors dominate the function of adrenergic activation in lateral amygdala. In this study, we investigated the action of β1-adrenergic receptor antagonist-metoprolol and β2-adrenergic receptor antagonist-butoxamine on the retention of conditioned fear memory and synaptic adaptation in the lateral amygdala of rats. We found metoprolol not butoxamine attenuated the reactivation-induced strengthening of fear retention and restored the impaired long-term depression in lateral amygdala. Intra-amygdala infusion of metoprolol not butoxamine attenuated reactivation-induced enhancement of fear retention. Our results suggest that β1-adrenergic receptor antagonist-metoprolol may be more suitable for the treatment of posttraumatic stress disorder.

Background/Aims: Acute kidney injury (AKI) is a serious complication of sepsis and has a high morbidity and mortality rate. Caspase-11 induces pyroptosis, a form of programmed cell death that plays a critical role in endotoxic shock, but its role in tubular epithelial cell death and whether it contributes to sepsis-associated AKI remains unknown. Methods: The caspase-11–/– mouse received an intraperitoneal injection of lipopolysaccharide (LPS, 40 mg/kg body weight). Caspase-11–/– renal tubular epithelial cells (RTECs) form C57BL caspase-11–/– mice were treated with LPS in vitro. The IL-1β ELISA kit and Scr assay kit were used to measure the level of interleukin-1β and serum creatinine. Annexin V-FITC assay and TUNEL staining assay were used to detect the cell death in different groups in vitro and in vivo. Western blot was performed to analyze the protein expression of caspase-11 and Gsdmdc1. Results: LPS-induced sepsis results in lytic death of RTECs, accompanied by increased expression of the pyroptosis-related proteins caspase-11 and Gsdmd. However, the increase in pyroptosis-related protein expression induced by LPS was attenuated with caspase-11 knockout, both in vitro and in vivo. Furthermore, when challenged with lethal doses of systemic LPS, pathologic abnormalities in renal structure, increased serum and kidney interleukin-1β, increased serum creatinine, and animal death were observed in wild-type mice but prevented in caspase-11–/– mice. Conclusions: Caspase-11-induced pyroptosis of RTECs is a key event during septic AKI, and targeting of caspase-11 in RTECs may serve as a novel therapeutic target in septic AKI.

Background Although aging increases susceptibility to acute kidney injury (AKI), whether the AKI risk and the association between AKI and adverse outcomes are age-dependent remain unclear in older adults. The current study aimed to identify whether AKI risk was age-dependent in older adults and to investigate whether the association between AKI and mortality increased with increasing age. Methods Medical records from 47,012 adult hospital admissions, including 30,194 older adults aged 60 or older, in two tertiary general hospitals were studied retrospectively. AKI was identified based on changes in blood creatinine levels according to the Kidney Disease: Improving Global Outcomes criteria. Results Among the total population and 30,194 older adult patients, the raw incidences of AKI were 8.2 and 8.3%, respectively. The curve of the age-grouped AKI incidence was “U-shaped”, which revealed a positive relationship between the AKI incidence and age among the older adults aged 75 years or older. This trend of the age-AKI relationship was supported by further multivariable analysis. After adjusting for the Charlson Comorbidity Index score, the AKI was associated with in-hospital mortality; however, the associations did not increase with increasing age. Conclusion The AKI risk does not increase with age in older adults, except for those aged 75 and above. The association between AKI and in-hospital death did not increase in an age-dependent manner in older adults. Trial registration This study was retrospectively registered at clinicaltrials.gov (NCT03054142) on February 13, 2017.

Mitochondrial damage in renal tubular epithelial cells (RTECs) is a hallmark of endotoxin-induced acute kidney injury (AKI). Forkhead box O1 (FOXO1) is responsible for regulating mitochondrial function and is involved in several kidney diseases. Here, we investigated the effect of FOXO1 on endotoxin-induced AKI and the related mechanism. In vivo, FOXO1 downregulation in mouse RTECs and mitochondrial damage were found in endotoxin-induced AKI. Overexpression of FOXO1 by kidney focal adeno-associated virus (AAV) delivery improved renal function and reduced mitochondrial damage. Peroxisome proliferator-activated receptor-γ coactivator 1-α (PGC1-α), a master regulator of mitochondrial biogenesis and function, was reduced in endotoxin-induced AKI, but the reduction was reversed by FOXO1 overexpression. In vitro, exposure to LPS led to a decline in HK-2 cell viability, mitochondrial fragmentation, and mitochondrial superoxide accumulation, as well as downregulation of FOXO1, PGC1-α, and mitochondrial complex I/V. Moreover, overexpression of FOXO1 in HK-2 cells increased HK-2 cell viability and PGC1-α expression, and it alleviated the mitochondrial injury and superoxide accumulation induced by LPS. Meanwhile, inhibition of FOXO1 in HK-2 cells by siRNA treatment decreased PGC1-α expression and HK-2 cell viability. Chromatin immunoprecipitation assays and PCR analysis confirmed that FOXO1 bound to the PGC1-α promoter in HK-2 cells. In conclusion, downregulation of FOXO1 in RTECs mediated endotoxin-induced AKI and mitochondrial damage. Overexpression of FOXO1 could improve renal injury and mitochondrial dysfunction, and this effect occurred at least in part as a result of PGC1-α signaling. FOXO1 might be a potential target for the prevention and treatment of endotoxin-induced AKI.

Diabetic kidney disease (DKD) is a serious and common complication of diabetes. Extracellular vesicles (EVs) have emerged as crucial vectors in cell-to-cell communication during the development of DKD. EVs may mediate intercellular communication between podocytes and proximal tubules. In this study, EVs were isolated from podocyte culture supernatants under high glucose (HG), normal glucose (NG), and iso-osmolality conditions, and then co-cultured with proximal tubular epithelial cells (PTECs). MicroRNAs (miRNA) sequencing was conducted to identify differentially expressed miRNAs of podocyte EVs and bioinformatics analysis was performed to explore their potential functions. The results showed that EVs secreted from HG-treated podocytes induced apoptosis of PTECs. Moreover, five differentially expressed miRNAs in response to HG condition were identified. Functional enrichment analysis revealed that these five miRNAs are likely involved in biological processes and pathways related to the pathogenesis of DKD. Overall, these findings demonstrate the pro-apoptotic effects of EVs from HG-treated podocytes on PTECs and provide new insights into the pathologic mechanisms underlying DKD.

Objective To develop a clinical model for predicting postoperative acute kidney injury (AKI) in patients of advanced age undergoing cardiac surgery. Methods A total of 848 patients (aged ≥ 60 years) undergoing cardiac surgery were consecutively enrolled. Among them, 597 were randomly selected for the development set and the remaining 251 for the validation set. AKI was the primary outcome. To develop a model for predicting AKI, visualized as a nomogram, we performed logistic regression with variables selected by Lasso regression analysis. The discrimination, calibration, and clinical usefulness of the new model were assessed and compared with those of Cleveland Clinic score and Simplified Renal Index (SRI) score in the validation set. Results The incidence of AKI was 61.8% in the development set. The new model included seven variables including preoperative serum creatinine, hypertension, preoperative uric acid, New York Heart Association classification ≥ 3, cardiopulmonary bypass time > 120 min, intraoperative red blood cell transfusion, and postoperative prolonged mechanical ventilation. In the validation set, the areas under the receiver operating characteristic curves for assessing discrimination of the new model, Cleveland Clinic score, and SRI score were 0.801, 0.670, and 0.627, respectively. Compared with the other two scores, the new model presented excellent calibration according to the calibration curves. Decision curve analysis presented the new model was more clinically useful than the other two scores. Conclusions We developed and validated a new model for predicting AKI after cardiac surgery in patients of advanced age, which may help clinicians assess patients' risk for AKI.

BACKGROUND: AKI is characterized by abrupt and reversible kidney dysfunction, and incomplete recovery leads to chronic kidney injury. Previous studies by us and others have indicated that macrophage infiltration and polarization play key roles in recovery from AKI. The role in AKI recovery played by IFN regulatory factor 4 (IRF4), a mediator of polarization of macrophages to the M2 phenotype, is unclear. METHODS: We used mice with myeloid or macrophage cell–specific deletion of Irf4 (MΦ Irf4 (−/−)) to evaluate Irf4’s role in renal macrophage polarization and development of fibrosis after severe AKI. RESULTS: Surprisingly, although macrophage Irf4 deletion had a minimal effect on early renal functional recovery from AKI, it resulted in decreased renal fibrosis 4 weeks after severe AKI, in association with less-activated macrophages. Macrophage Irf4 deletion also protected against renal fibrosis in unilateral ureteral obstruction. Bone marrow–derived monocytes (BMDMs) from MΦ Irf4 (−/−) mice had diminished chemotactic responses to macrophage chemoattractants, with decreased activation of AKT and PI3 kinase and increased PTEN expression. PI3K and AKT inhibitors markedly decreased chemotaxis in wild-type BMDMs, and in a cultured macrophage cell line. There was significant inhibition of homing of labeled Irf4 (−/−) BMDMs to postischemic kidneys. Renal macrophage infiltration in response to AKI was markedly decreased in MΦ Irf4 (−/−) mice or in wild-type mice with inhibition of AKT activity. CONCLUSIONS: Deletion of Irf4 from myeloid cells protected against development of tubulointerstitial fibrosis after severe ischemic renal injury in mice, due primarily to inhibition of AKT-mediated monocyte recruitment to the injured kidney and reduced activation and subsequent polarization into a profibrotic M2 phenotype.

We described protein A immunoadsorption combination with immunosuppressive treatment improved rapidly a patient with Neuropsychiatric systemic lupus erythematosus.

Background Metabolic syndrome (MS) and diabetes mellitus (DM) are risk factors for cardiovascular diseases in general population. However, there was a paucity of studies investigating their impact in primary glomerular diseases (PGD). Hypothesis MS and concomitant DM are associated with higher risk of cardiovascular comorbidity in PGD. Methods In a retrospective observational design, we analyzed 3622 hospitalized adult PGD patients and compared the prevalence of cardiovascular comorbidity in non‐MS, MS with and without DM. Risk factors for cardiovascular comorbidity were identified using univariate and multivariate logistic regression. Results Among 3622 PGD patients, 308 (8.5%) cases accompanied with MS, including 180 (5.0%) patients with DM and 128 (3.5%) without DM. One hundred and sixty four (4.5%) cases coexisted with cardiovascular comorbidity. Patients with MS and concomitant DM exhibited a higher prevalence of cardiovascular comorbidity than those without MS stratified by estimated glomerular filtration rate and pathological types. Logistic regression showed that MS and concomitant DM (OR: 2.496, 95% CI: 1.600‐3.894, P

Left atrial appendage (LAA) dysfunction identified by transesophageal echocardiography (TEE) is a powerful predictor of stroke in patients with atrial fibrillation (AF). The aim of our study is to assess if there is a correlation between the left atrial (LA) functional parameter and LAA dysfunction in the AF patients. This cross-sectional study included a total of 249 Chinese AF patients who did not have cardiac valvular diseases and were undergoing cardiac ablation. TEE was performed in all the patients who were categorized into two groups according to their left atrial appendage (LAA) function. A total of 120 of the 249 AF patients had LAA dysfunction. Univariate and multivariate logistic regression was conducted to assess the independent factors that correlated with the LAA dysfunction. Different predictive models for the LAA dysfunction were compared with the receiver operating characteristic (ROC) curve. The final ROC curve on the development and validation datasets was drawn based on the calculation of each area under the curves (AUC). Univariate and multivariate analysis showed that the peak left atrial strain (PLAS) was the most significant factor that correlated with the LAA dysfunction. PLAS did not show inferiority amongst all the models and revealed strong discrimination ability on both the development and validation datasets with AUC 0.818 and 0.817. Our study showed that a decrease in PLAS is independently associated with LAA dysfunction in the AF patients.

Phosphatase and tensin homolog deleted on chromosome 10 (PTEN) has proven to be downregulated in podocytes challenged with high glucose (HG), and knockout of PTEN in podocytes aggravated the progression of diabetic kidney disease (DKD). However, whether podocyte-specific knockin of PTEN protects the kidney against hyperglycemia in vivo remains unknown. The inducible podocyte-specific PTEN knockin (PPKI) mice were generated by crossing newly created transgenic loxP-stop- loxP-PTEN mice with podocin-iCreERT2 mice. Diabetes mellitus was induced in mice by intraperitoneal injection of streptozotocin at a dose of 150 mg/kg. In vitro, small interfering RNA and adenovirus interference were used to observe the role of PTEN in HG-treated podocytes. Our data demonstrated that PTEN was markedly reduced in the podocytes of patients with DKD and focal segmental glomerulosclerosis, as well as in those of db/db mice. Interestingly, podocyte-specific knockin of PTEN significantly alleviated albuminuria, mesangial matrix expansion, effacement of podocyte foot processes, and incrassation of glomerular basement membrane in diabetic PPKI mice compared with wild-type diabetic mice, whereas no alteration was observed in the level of blood glucose. The potential renal protection of overexpressed PTEN in podocytes was partly attributed with an improvement in autophagy and motility and the inhibition of apoptosis. Our results showed that podocyte-specific knockin of PTEN protected the kidney against hyperglycemia in vivo , suggesting that targeting PTEN might be a novel and promising therapeutic strategy against DKD.

Insufficient autophagy in podocytes is related to podocyte injury in diabetic nephropathy (DN). Advanced glycation end-products (AGEs) are major factors of podocyte injury in DN. However, the role and mechanism of AGEs in autophagic dysfunction remain unknown. We investigated autophagic flux in AGE-stimulated cultured podocytes using multiple assays: western blotting, reverse transcription-quantitative PCR, immunofluorescence staining, and electron microscopy. We also utilized chloroquine and a fluorescent probe to monitor the formation and turnover of autophagosomes. Mice of the db/db strain were used to model diabetes mellitus (DM) with high levels of AGEs. To mimic DM with normal levels of AGEs as a control, we treated db/db mice with pyridoxamine to block AGE formation. AGEs impaired autophagic flux in the cultured podocytes. Compared with db/db mice with normal AGEs but high glucose levels, db/db mice with high AGEs and high glucose levels exhibited lower autophagic activity. Aberrant autophagic flux was related to hyperactive mammalian target of rapamycin (mTOR), a major suppressor of autophagy. Pharmacologic inhibition of mTOR activity restored impaired autophagy. AGEs inhibited the nuclear translocation and activity of the pro-autophagic transcription factor EB (TFEB) and thus suppressed transcription of its several autophagic target genes. Conversely, TFEB overexpression prevented AGE-induced autophagy insufficiency. Attenuating mTOR activity recovered TFEB nuclear translocation under AGE stimulation. Co-immunoprecipitation assays further demonstrated the interaction between mTOR and TFEB in AGE-stimulated podocytes and in glomeruli from db/db mice. In conclusion, AGEs play a crucial part in suppressing podocyte autophagy under DM conditions. AGEs inhibited the formation and turnover of autophagosomes in podocytes by activating mTOR and inhibiting the nuclear translocation of TFEB. © 2018 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of Pathological Society of Great Britain and Ireland.

We present the case of a 42‐year‐old female patient who attempted suicide by taking approximately 100 tablets of metformin (500 mg). Laboratory tests revealed severe lactic acidosis with lactate levels of 24 mmol/L and pH of 7.09. The patient was treated with high‐volume continuous venovenous hemodiafiltration (CVVH) and resin‐sorbent hemoperfusion. Metformin concentrations were measured by high‐performance liquid chromatography during CVVH and hemoperfusion treatment. Before extracorporeal treatment, the plasma metformin concentration was 208.5 mg/L. After CVVH treatment for 24 h, the plasma metformin concentration had decreased to 13.9 mg/L. Resin‐based sorbent hemoperfusion plus CVVH treatment had reduced the metformin plasma concentration by 61.8% after 3 h. After 7 days, the patient's laboratory tests and clinical syndrome were improved, and she was discharged from hospital. We provide evidence that CVVH plus hemoperfusion is effective in eliminating metformins and metabolic products.

Emotional memory deficit is a well-known complication in early Parkinson's disease. However, its molecular mechanism is still not well known. To address this issue, we examined the cue-related fear-conditioning task and long-term potentiation (LTP) of the thalamus to the lateral amygdala in rats treated with low doses of reserpine (Res). We found that low-dose Res treatment impaired emotional memory and LTP. We also found that exogenous upregulation of norepinephrine (NE) ameliorated the impairment of LTP by facilitating β-adrenergic receptors. Finally, acute treatment with NE or desipramine rescued the impaired emotional memory induced by a low-dose of Res. These results imply a pivotal role for NE in synaptic plasticity and associative fear memory in rats treated with low doses of Res and suggest that desipramine is a potential candidate for treating Parkinson's disease-related emotional memory deficit.

Apoptosis and necroptosis occur in renal tubular epithelial cell (RTEC) death in acute kidney injury (AKI), and may be regulated by several methods. The present study identified a protective effect of necrostatin‑1 (Nec‑1) on RTECs via a flow-control-like effect. The results established a hypoxic‑ischemic injury model of rat NRK‑52E RTECs using tumour necrosis factor‑α followed by ATP depletion with antimycin A and the pan-caspase pathway blocker, benzyloxycarbonyl-Val-Ala-Asp-fluoro-methylketone. Following pre‑treatment of cells with Nec‑1, cell organelle inflation, fragmentation inhibition and improved cell viability were observed with a parallel reduced expression of microtubule‑associated protein 1A/1B‑light chain 3‑II. Nec‑1 was involved in flow control in the process of cell injury and death. In conclusion, the present study indicated that Nec‑1 provides a protective effect and serves an important role in the prevention of AKI in an NRK‑52E cell model. Further studies will be required to fully investigate the role of Nec‑1 in the development of AKI in vivo.

Background: Red blood cell distribution width (RDW) is a cardiovascular biomarker. We evaluated the association between RDW and cerebral stroke risk in hemodialysis patients.Methods: A cohort of 44...

Background: Alzheimer’s disease (AD) is the most common neurodegenerative disease, and the accumulation of amyloid-β is the initial process in AD. MicroRNAs (miRNAs) are widely known as key regulators of the accumulation of amyloid-β in AD. This study analyzed the potential effects and possible internal mechanisms of miR-340 on AD. Methods: The expression of miR-340 in senescence-accelerated mouse prone-8 (SAMP8) mouse and senescence-accelerated mice/resistant-1 (SAMR1) mouse was evaluated by qRT-PCR (quantitative real-time polymerase chain reaction). The expression of β-site amyloid precursor protein cleaving enzyme 1 (BACE1) was determined by qRT-PCR and western blot. The binding ability between miR-340 and BACE1 was verified by dual-luciferase reporter assay. In vitro cell model of AD was established in human neuroblastoma SH-SY5Y cells transfected with Swedish mutant form of amyloid precursor protein (APPswe). The effect of miR-340 on the accumulation of amyloid- β was investigated by western blot analysis. Flow cytometry was conducted to detect cell apoptosis. Results: MiR-340 was down-regulated in the hippocampus of AD model SAMP8 mouse compared to SAMR1 mouse, while BACE1 was up-regulated in SAMP8, suggesting a negative correlation between miR-340 and BACE1 in SAMP8 mouse. MiR-340 could directly bind with BACE1, and over-expression of miR-340 decreased expression of BACE1 in SH-SY5Y/APPswe cells. MiR- 340 reduced the accumulation of amyloid-β and suppressed cell apoptosis through targeting BACE1 in SH-SY5Y/APPswe cells. Conclusion: MiR-340 was downregulated in AD and reduced the accumulation of amyloid-β through targeting BACE1, suggesting a potential therapeutic target for AD.

Aim Phospholipase A2 receptor (PLA2R) is a target antigen for idiopathic membranous nephropathy (IMN). However, the association between renal PLA2R antigen and disease prognosis had not been fully investigated. In addition, there was a paucity of studies investigating the difference of therapeutic effects between cyclophosphamide and cyclosporine A in PLA2R‐associated IMN. Methods This retrospective cohort study recruited 300 eligible patients diagnosed with biopsy‐proven IMN between September 2015 and July 2018 in Guangdong Provincial People's Hospital. The remission of proteinuria was compared between PLA2R‐associated and non‐PLA2R‐associated IMN. The difference of therapeutic effects between cyclophosphamide and cyclosporine A were also investigated in PLA2R‐associated IMN. Results The positive rate of renal PLA2R antigen in recruited IMN patients was 82.3%. Non‐PLA2R‐associated IMN patients had a higher probability to achieve remission than PLA2R‐associated IMN patients (Log–rank test, P = .013). Multivariate COX analysis showed that renal PLA2R antigen was an independent risk factor for not achieving remission in IMN patients (Hazard Ratio: 1.619; 95% confidence interval: 1.133 to 2.313; P = .008). In PLA2R‐associated IMN, patients receiving cyclophosphamide had a higher probability to achieve remission compared with those receiving cyclosporine A (Log–rank test, P = .018) while there was no difference in renal survival. Multivariate COX regression analysis showed that compared with cyclosporine A, patients receiving cyclophosphamide had a higher probability to achieve remission. Conclusion Phospholipase A2 receptor ‐associated IMN patients had a lower probability to achieve remission compared with non‐PLA2R‐associated IMN. Compared with cyclosporine A, cyclophosphamide exerted better therapeutic effects in remission of proteinuria and may be the preferred immunosuppressant for PLA2R‐associated IMN. SUMMARY AT A GLANCE This article highlighted the prognostic value of intra‐renal phospholipase A2 receptor deposition in idiopathic membranous nephropathy (IMN). Renal phospholipase A2 receptor (PLA2R)‐associated IMN patients had a lower probability to achieve remission compared with non‐PLA2R‐associated IMN.

Ischemia-reperfusion (I/R)-induced acute kidney injury (I/R-AKI) favors mitochondrial permeability transition pore (mPTP) opening and subsequent cell death. Cyclophilin D (CypD) is an essential component of the mPTP, and recent findings have implicated the p53-CypD complex in cell death. To evaluate the role of p53-CypD after I/R-AKI, we tested the hypothesis that the p53-CypD complex mediates renal tubular cell apoptosis in I/R-AKI via mPTP opening. Expression of p53 and cleaved caspase-3 was significantly increased in rats subjected to I/R-AKI compared with normal controls and sham-operated controls. The underlying mechanisms were determined using an in vitro model of ATP depletion. Inhibition of mPTP opening using the CypD inhibitor cyclosporin A or siRNA for p53 in ATP-depleted HK-2 cells prevented mitochondrial membrane depolarization and reduced apoptosis. Furthermore, p53 bound to CypD in ATP-depleted HK-2 cells. These results suggest that the p53-CypD complex mediates renal tubular cell apoptosis in I/R-AKI via mPTP opening.

Renal tubular epithelial cell apoptosis is an important pathological mechanism of septic acute kidney injury (AKI). Endotoxin, also known as lipopolysaccharide (LPS), has a key role in septic AKI and can directly induce tubular epithelial cell apoptosis. The upregulation of receptor‑interacting protein kinase 3 (RIPK3) in tubular epithelial cells has been reported in septic AKI, with RIPK3 mediating apoptosis in several cell types. In the present study, the effect of RIPK3 on endotoxin‑induced AKI was investigated in mouse tubular epithelial cell apoptosis in vitro and in vivo. It was found that the expression of RIPK3 was markedly increased in endotoxin‑induced AKI. Endotoxin‑induced AKI and tubular epithelial cell apoptosis could be attenuated by GSK'872, a RIPK3 inhibitor. LPS stimulation also upregulated RIPK3 expression in tubular epithelial cells in a time‑dependent manner. Both RIPK3 inhibitor and small interfering RNA (siRNA) targeting RIPK3 reduced LPS‑induced tubular epithelial cell apoptosis in vitro. The expression of the proapoptotic protein Bax was induced by LPS and reversed by GSK'872 or RIPK3‑siRNA. The present study revealed that RIPK3 mediated renal tubular cell apoptosis in endotoxin‑induced AKI. RIPK3 may be a potential target for the prevention of renal tubular cell apoptosis in endotoxin‑induced AKI.

Background Two-dimensional speckle-tracking echocardiography (2D-STE) enables objective assessment of left atrial (LA) deformation through the analysis of myocardial strain, which can be measured by different speckle-tracking software. The aim of this study was to compare the consistency of 3 different commercially available software, which include vendor-specific software for measuring left ventricle (VSSLV), vendor-independent software packages for measuring LV strain (VISLV) and vendor-independent software packages for measuring LA strain (VISLA). Methods Sixty-four subjects (mean age: 44 ± 16 years, 50% males) underwent conventional echocardiograms using a GE Vivid 9 (GE Ultrasound, Horten, Norway) cardiac ultrasound system. Standard apical 4 and 2 chamber views of the left atrium were obtained in each subject with a frame-rate range of 40–71 frames/s. LA strain during the contraction phase (Sct), conduit phase (Scd), reservoir phase (Sr = Sct + Scd) were analyzed by 2 independent observers and 3 different software. Results Sct, Scd, Sr were, respectively, − 11.26 ± 2.45%, − 16.77 ± 7.06%, and 28.03 ± 7.58% with VSSLV, − 14.77 ± 3.59%, − 23.17 ± 10.33%, and 38.23 ± 10.99% with VISLV, and − 14.80 ± 3.88%, − 23.94 ± 10.48%, and 38.73 ± 11.56% when VISLA was used. A comparison of strain measurements between VSSLV and VIS (VISLV and VISLA) showed VIS had significantly smaller mean differences and narrower limits of agreement. Similar results were observed in the coefficient of variation (CV) for measurements between VSSLV and VIS (VISLV and VISLA). Comparison of the intra-class correlation coefficients (ICCs) indicated that measurement reliability was weaker with VSSLV (ICC 0.9). For intra-observer ICCs, VISLA > VSSLV = VISLV. For inter-observer ICCs, VSSLV > VISLA > VISLV. Conclusions Software measurement results of LA strain vary considerably. We recommended not measuring LA strain across vendor platforms. Electronic supplementary material The online version of this article (10.1186/s12947-019-0158-y) contains supplementary material, which is available to authorized users.

Podocyte depletion is a central pathological mechanism of diabetic nephropathy (DN). Hyperglycemia induced podocyte apoptosis, resulting in podocyte depletion. However, the crucial mechanism of hyperglycemia-induced podocyte apoptosis remains poorly understood. In this study, we evaluated the expression of septin 7, a GTP-binding protein, in glomerular podocytes of patients and mice with DN, and investigated the pro-apoptotic effect of septin 7 on high glucose (HG) induced podocyte apoptosis in vitro. We found septin 7 expression was markedly increased not only in glomerular podocytes of patients and db/db mice with DN but also in cultured podocytes with HG stimulation. Knocking down septin 7 with siRNA could attenuate HG induced podocytes apoptosis and excessive intracellular Ca2+ concentration. This study revealed septin7 may potentially play a proapoptotic role in podocyte under diabetic conditions and may provide a potential target for preventing podocyte apoptosis in DN.

Extensive kidney fibrosis occurs in several types of chronic kidney diseases. PBI-4050, a potentially novel first-in-class orally active low–molecular weight compound, has antifibrotic and antiinflammatory properties. We examined whether PBI-4050 affected the progression of diabetic nephropathy (DN) in a mouse model of accelerated type 2 diabetes and in a model of selective tubulointerstitial fibrosis. eNOS–/– db/db mice were treated with PBI-4050 from 8–20 weeks of age (early treatment) or from 16–24 weeks of age (late treatment). PBI-4050 treatment ameliorated the fasting hyperglycemia and abnormal glucose tolerance tests seen in vehicle-treated mice. In addition, PBI-4050 preserved (early treatment) or restored (late treatment) blood insulin levels and increased autophagy in islets. PBI-4050 treatment led to significant improvements in lifespan in the diabetic mice. Both early and late PBI-4050 treatment protected against progression of DN, as indicated by reduced histological glomerular injury and albuminuria, slow decline of glomerular filtration rate, and loss of podocytes. PBI-4050 inhibited kidney macrophage infiltration, oxidative stress, and TGF-β–mediated fibrotic signaling pathways, and it also protected against the development of tubulointerstitial fibrosis. To confirm a direct antiinflammatory/antifibrotic effect in the kidney, further studies with a nondiabetic model of EGFR-mediated proximal tubule activation confirmed that PBI-4050 dramatically decreased the development of the associated tubulointerstitial injury and macrophage infiltration. These studies suggest that PBI-4050 attenuates development of DN in type 2 diabetes through improvement of glycemic control and inhibition of renal TGF-β–mediated fibrotic pathways, in association with decreases in macrophage infiltration and oxidative stress.

The aim of the present study was to investigate the protective effect of the NADPH oxidase inhibitor, diphenyleneiodonium (DPI) against necroptosis in renal tubular epithelial cells. A necroptosis model of HK-2 cells was established using tumor necrosis factor-α, benzyloxycarbonyl-Val-Ala-Asp-fluoromethylketone and antimycin A (collectively termed TZA), as in our previous research. The necroptosis inhibitor, necrostatin-1 (Nec-1) or the NADPH oxidase inhibitor, DPI were administered to the necroptosis model. Production of reactive oxygen species (ROS) was detected by dichlorodihydrofluorescein diacetate in the different groups, and the manner of cell death was identified by flow cytometry. Western blot analysis was used to determine the levels of phosphorylation of receptor-interacting protein kinase 3 (RIP-3) and mixed lineage kinase domain-like (MLKL), which are essential to necroptosis. The results revealed that TZA increased the percentages of propidium iodide-positive HK-2 cells from 1.22±0.69 to 8.98±0.73% (P

The aim of the present study was to investigate the protective effect of necrostatin‑1 (Nec‑1) in sepsis‑associated acute kidney injury (SA‑AKI). An SA‑AKI mouse model was established through an intraperitoneal injection of lipopolysaccharide (LPS), and Nec‑1 was administered to the mice prior to the establishment of SA‑AKI. Renal function and histological changes were evaluated, and the expression levels of microtubule‑associated protein light chain 3‑II (LC3‑II) and p62, as markers of autophagic flux, were detected. Autophagosomes and autolysosomes in renal tubular epithelial cells were also identified using electron microscopy. Pretreatment with Nec‑1 could attenuate the LPS‑induced increases in the concentrations of blood urea nitrogen (LPS+Nec‑1 vs. LPS group, 14.15±4.14 mmol/l vs. 32.54±5.46 mmol/l, respectively; P

// Yuanhan Chen 1 , Zhen Xie 2 , Chenggen Xiao 1, 3 , Min Zhang 4 , Zhilian Li 1 , Jianteng Xie 1 , Yusheng Zhang 5 , Xingchen Zhao 1, 6 , Pengfei Zeng 5 , Liyi Mo 1, 7 , Xinling Liang 1 , Wei Shi 1 1 Division of Nephrology, Guangdong General Hospital, Guangdong Academy of Medical Sciences, Guangzhou, China 2 Department of Dermatology, Sichuan Academy of Medical Sciences & Sichuan Provincial People’s Hospital, Chengdu, China 3 Division of Nephrology, Xiangya Hospital, Central South University, Hunan, China 4 Department of Gastroenterology, The Sixth Affiliated Hospital, Sun Yat-Sen University, Guangzhou, China 5 Second Division of Internal Medicine, Wuhua People’s Hospital, Guangdong, China 6 Southern Medical University, Guangzhou, China 7 Department of Nephrology, Dongguan People’s Hospital, Guangdong Province, China Correspondence to: Wei Shi, email: ssweicn@163.com Xinling Liang, email: xinlingliang@139.com Keywords: indoleamine 2,3-dioxygenase, kynurenine to tryptophan ratio, hemodialysis, immune tolerance, infection Received: September 18, 2016 Accepted: January 24, 2017 Published: February 25, 2017 ABSTRACT Indoleamine 2,3-dioxygenase (IDO) has emerged as a pivotal enzyme for mediating immune tolerance. Because IDO metabolizes tryptophan into kynurenine, the plasma kynurenine/tryptophan (Kyn/Trp) ratio has been widely used as a marker of systemic IDO. Here, we evaluated the clinical value of using the plasma Kyn/Trp ratio to estimate cell-mediated immune responses to tuberculin skin testing and risk of new bacterial infection. We also compared the Kyn/Trp ratio to a novel IDO marker, the IDO median fluorescence index (MFI) of peripheral blood mononuclear cells, which was determined by flow cytometry. In 228 patients from two hemodialysis centers, the two IDO markers were higher in patients than in healthy controls but were not correlated with each other. In vitro experiments demonstrated that peripheral blood mononuclear cells could not metabolize tryptophan into kynurenine, indicating that the increased Kyn/Trp ratio was IDO-independent. Skin induration diameters of tuberculin skin testing were correlated with the IDO MFI (negatively), but not the Kyn/Trp ratio. Further, in a 24-month prospective cohort, the Kyn/Trp ratio was not correlated with clinical infection. Alternatively, patients with a higher IDO MFI had a lower accumulative infection-free survival rate. Using a Cox proportional hazard model, it was also revealed that a higher IDO MFI was significantly associated with new bacterial infection. Taken together, these results indicate that the Kyn/Trp ratio is not a reliable circulating IDO marker in hemodialysis patients. However, the IDO MFI reflects an immunocompromised state and thus might be a potential clinical marker of bacterial infection.

BackgroundThe correlation between proteinuria and contrast-induced acute kidney injury (CI-AKI) in patients with cerebrovascular disease is still unknown.ObjectiveTo determine whether proteinuria is a risk factor for CI-AKI and death in patients with stroke undergoing cerebral angiography.MethodsData from 2015 patients with stroke undergoing cerebral angiography between January 2009 and December 2013 were retrospectively collected. Clinical parameters were obtained from the hospital's computerized database. All variables were analyzed by univariate analysis and multivariate logistic regression analysis.ResultsCI-AKI was seen in 85 patients (4.2%). After adjustment for potential confounding risk factors, patients with proteinuria had a fivefold higher risk of CI-AKI than patients without proteinuria (OR=5.74; 95% CI 2.23 to 14.83; p2, anemia, and a high National Institute of Health Stroke Scale score. Proteinuria did not increase in-hospital mortality (OR=1.25; 95% CI 0.49 to 3.17; p=0.639) but did increase 1-year mortality (HR=2.30, 95% CI 1.55 to 3.41, pConclusionsProteinuria is an independent risk factor for CI-AKI and 1-year mortality in patients with stroke undergoing cerebral angiography. More attention should be paid to the development of CI-AKI in patients with stroke with proteinuria.

Podocyte apoptosis is a major mechanism that leads to proteinuria in many chronic kidney diseases. However, the concert mechanisms that cause podocyte apoptosis in these kidney diseases are not fully understood. The Rho family of small GTPases has been shown to be required in maintaining podocyte structure and function. Recent studies have indicated that podocyte-specific deletion of Cdc42 in vivo, but not of RhoA or Rac1, leads to congenital nephrotic syndrome and glomerulosclerosis. However, the underlying cellular events in podocyte controlled by Cdc42 remain unclear. Here, we assessed the cellular mechanisms by which Cdc42 regulates podocyte apoptosis. We found that the expression of Cdc42 and its activity were significantly decreased in high glucose-, lipopolysaccharide- or adriamycin-injured podocytes. Reduced Cdc42 expression in vitro and in vivo by small interfering RNA and selective Cdc42 inhibitor ML-141, respectively, caused podocyte apoptosis and proteinuria. Our results further demonstrated that insufficient Cdc42 or Nwasp, its downstream effector, could decrease the mRNA and protein expression of YAP, which had been regarded as an anti-apoptosis protein in podocyte. Moreover, our data indicated that the loss of stress fibers caused by Cdc42/Nwasp deficiency also decreased Yes-associated protein (YAP) mRNA and protein expression, and induced podocyte apoptosis. Podocyte apoptosis induced by Cdc42/Nwasp/stress fiber deficiency was significantly inhibited by overexpressing-active YAP. Thus, the Cdc42/Nwasp/stress fibers/YAP signal pathway may potentially play an important role in regulating podocyte apoptosis. Maintaining necessary Cdc42 would be one potent way to prevent proteinuria kidney diseases.