Aberrant NAD synthetic flux in podocytes under diabetic conditions and effects of indoleamine 2,3-dioxygenase on promoting de novo NAD synthesis.

Nicotinamide adenine dinucleotide (NAD) is an essential coenzyme in the kidney. The first step in de novo NAD synthesis is regulated by indoleamine 2,3-dioxygenase (IDO), a tryptophan-catabolizing enzyme. Here, we investigated NAD synthetic flux and NAD levels in podocytes under diabetic conditions. We also studied the effects of IDO overexpression on NAD synthetic flux and high glucose (HG)-induced podocyte injury. NAD synthetases in the de novo, Preiss-Handler and salvage pathways were analyzed using in vivo single-nucleus RNA sequencing datasets (GSE131882) of control and diabetic kidney disease (DKD). The mRNA levels of these NAD synthetases were measured in vitro in HG-treated podocytes. The effects of IDO on NAD synthesis were examined by transducing cultured podocytes with an adenovirus encoding IDO, and apoptosis, podocyte markers and mobility were investigated. Cellular transcriptome analysis revealed that control podocytes had relatively low levels of NAD synthetases. In DKD podocytes, de novo NAD synthetase levels were further downregulated. IDO levels were virtually undetectable and did not increase in DKD. In vitro experiments confirmed aberrant de novo NAD synthetic flux and decreased IDO levels in HG-treated podocytes. Overexpression of IDO promoted NAD de novo synthesis, reduced NAD-bypass metabolic enzyme, increased NAD content and recovered podocyte injury markers under diabetic conditions. Taken together, our findings suggest that the de novo NAD synthetic flux is aberrant in DKD, and IDO promotes de novo NAD synthesis and NAD levels, as well as alleviates injury in HG-treated podocytes.

Growth associated protein 43 deficiency promotes podocyte injury by activating the calmodulin/calcineurin pathway under hyperglycemia.

Podocyte injury is a crucial factor in the pathogenesis of diabetic kidney disease (DKD), and finding potential therapeutic interventions that can mitigate podocyte injury holds significant clinical relevance. This study was to elucidate the role of growth associated protein-43(Gap43) in podocyte injury of high glucose (HG). We confirmed the expression of Gap43 in human glomerulus and found that Gap43 expression was downregulated in podocytes of patients with DKD and HG-treated podocytes in vitro. Gap43 knockdown in podocytes promoted podocyte apoptosis, increased migration ability and decreased nephrin expression, while overexpression of Gap43 markedly suppressed HG-induced injury. Moreover, the increased expression and activity of calcineurin (CaN) were also abrogated by overexpression Gap43 in HG. Pretreatment with a typical CaN inhibitor FK506 in Gap43 knockdown podocytes restored the injury. Mechanistically, co-immunoprecipitation experiments suggested that Gap43 could bind to calmodulin (CaM). Pull-down assay further demonstrated that Gap43 and CaM directly interacts with each other via amino acids 30-52 of Gap43 and amino acids 133-197 of CaM. In addition, we also identified Pax5 as potential transcription inhibitor factor mediating Gap43 expression. In conclusion, the study indicated that the Gap43/CaM-CaN pathway may be exploited as a promising therapeutic target for protecting against podocyte injury in high glucose.

Role of TFEB in regulation of the podocyte actin cytoskeleton.

Podocyte injury is linked to the pathogenesis and progression of renal disease. The Transcription Factor EB (TFEB), a master regulator of the autophagy and lysosomal pathways, has been found to exert cell- and tissue-specific biological function. To explore TFEB function and underlying mechanisms in podocytes, a total of 4645 differentially expressed genes (DEGs) were detected in TFEB-knockdown mouse podocytes by transcriptome sequencing. Gene Ontology, Kyoto Encyclopedia of Genes and Genomes, and Ingenuity Pathway Analysis showed that, apart from the enrichment in autophagy and lysosomal pathways, DEGs were enriched in cytoskeleton structure (Actin Cytoskeleton, Focal Adhesion, and Adherens Junction), as well as cytoskeleton regulatory molecular signaling (Hippo and Rho GTPase Signaling). In vitro, TFEB knockdown resulted in podocyte cytoskeletal rearrangement, which was disorganized with cortical distribution of actin filaments. Further, TFEB knockdown decreased mRNA and protein levels of Synaptopodin and led to the rearrangement of Synaptopodin. Inhibition of TFEB decreased mRNA levels for proteins involved in actin cytoskeleton dynamics. Moreover, apoptosis was increased by TFEB knockdown in podocyte. In summary, this study initiated a comprehensive analysis of the role of TFEB in podocyte function and the potential underlying mechanisms, and identified a novel role for TFEB in regulation of the podocyte actin cytoskeleton.

The value of the ACEF II score in Chinese patients with elective and non-elective cardiac surgery.

OBJECTIVE: To evaluate the value of the ACEF II score in predicting postoperative hospital death and acute kidney injury requiring dialysis (AKI-D) in Chinese patients. METHODS: This retrospective study included adult patients who underwent cardiopulmonary bypass open heart surgery between January 2010 and December 2015 at Guangdong Provincial People's Hospital. ACEF II was evaluated to predict in-hospital death and AKI-D using the Hosmer-Lemeshow goodness of fit test for calibration and area under the receiver operating characteristic (ROC) curve for discrimination in non-elective and elective cardiac surgery. RESULTS: A total of 9748 patients were included. Among them, 1080 underwent non-elective surgery, and 8615 underwent elective surgery. Mortality was 1.8% (177/9748). In elective surgery, the area under the ROC (AUC) of the ACEF II score was 0.704 (95% CI: 0.648-0.759), similar to the ACEF score of 0.709 (95% CI: 0.654-0.763). In non-elective surgery, the AUC of the ACEF II score was 0.725 (95% CI: 0.663-0.787), higher than the ACEF score (AUC = 0.625, 95% CI: 0.553-0.697). The incidence of AKI-D was 3.5% (345/9748). The AUC of the ACEF II score was 0.718 (95% CI: 0.687-0.749), higher than the ACEF score (AUC = 0.626, 95% CI: 0.594-0.658). CONCLUSION: ACEF and ACEF II have poor discrimination ability in predicting AKI-D in non-elective surgery. The ACEF II and ACEF scores have the same ability to predict in-hospital death in elective cardiac surgery, and the ACEF II score is better in non-elective surgery. The ACEF II score can be used to assess the risk of AKI-D in elective surgery in Chinese adults.

NFAT inhibitor 11R-VIVIT ameliorates mouse renal fibrosis after ischemia-reperfusion-induced acute kidney injury.

Acute kidney injury (AKI) with maladaptive tubular repair leads to renal fibrosis and progresses to chronic kidney disease (CKD). At present, there is no curative drug to interrupt AKI-to-CKD progression. The nuclear factor of the activated T cell (NFAT) family was initially identified as a transcription factor expressed in most immune cells and involved in the transcription of cytokine genes and other genes critical for the immune response. NFAT2 is also expressed in renal tubular epithelial cells (RTECs) and podocytes and plays an important regulatory role in the kidney. In this study, we investigated the renoprotective effect of 11R-VIVIT, a peptide inhibitor of NFAT, on renal fibrosis in the AKI-to-CKD transition and the underlying mechanisms. We first examined human renal biopsy tissues and found that the expression of NFAT2 was significantly increased in RTECs in patients with severe renal fibrosis. We then established a mouse model of AKI-to-CKD transition using bilateral ischemia-reperfusion injury (Bi-IRI). The mice were treated with 11R-VIVIT (5 mg/kg, i.p.) on Days 1, 3, 10, 17 and 24 after Bi-IRI. We showed that the expression of NFAT2 was markedly increased in RTECs in the AKI-to-CKD transition. 11R-VIVIT administration significantly inhibited the nuclear translocation of NFAT2 in RTECs, decreased the levels of serum creatinine and blood urea nitrogen, and attenuated renal tubulointerstitial fibrosis but had no toxic side effects on the heart and liver. In addition, we showed that 11R-VIVIT administration alleviated RTEC apoptosis after Bi-IRI. Consistently, preapplication of 11R-VIVIT (100 nM) and transfection with NFAT2-targeted siRNA markedly suppressed TGFß-induced HK-2 cell apoptosis in vitro. In conclusion, 11R-VIVIT administration inhibits IRI-induced NFAT2 activation and prevents AKI-to-CKD progression. Inhibiting NFAT2 may be a promising new therapeutic strategy for preventing renal fibrosis after IR-AKI.

Hospital-Acquired Acute Kidney Injury in Older Patients: Clinical Characteristics and Drug Analysis.

BACKGROUND: Information on older patients with hospital-acquired acute kidney injury (HA-AKI) and use of drugs is limited. AIM: This study aimed to assess the clinical characteristics, drug uses, and in-hospital outcomes of hospitalized older patients with HA-AKI. METHODS: Patients aged ≥65 years who were hospitalized in medical wards were retrospectively analyzed. The study patients were divided into the HA-AKI and non-AKI groups based on the changes in serum creatinine. Disease incidence, risk factors, drug uses, and in-hospital outcomes were compared between the groups. RESULTS: Of 26,710 older patients in medical wards, 4,491 (16.8%) developed HA-AKI. Older patients with HA-AKI had higher rates of multiple comorbidities and Charlson Comorbidity Index score than those without AKI (p < 0.001). In the HA-AKI group, the proportion of patients with prior use of drugs with possible nephrotoxicity was higher than that of patients with prior use of drugs with identified nephrotoxicity (p < 0.05). The proportions of patients with critical illness, use of nephrotoxic drugs, and the requirements of intensive care unit treatment, cardiopulmonary resuscitation, and dialysis as well as in-hospital mortality and hospitalization duration and costs were higher in the HA-AKI than the non-AKI group; these increased with HA-AKI severity (all p for trend <0.001). With the increase in the number of patients with continued use of drugs with possible nephrotoxicity after HA-AKI, the clinical outcomes showed a tendency to worsen (p < 0.001). Moreover, HA-AKI incidence (adjusted odds ratio [OR], 10.26; 95% confidence interval (CI), 8.27-12.74; p < 0.001), and nephrotoxic drugs exposure (adjusted OR, 1.76; 95% CI, 1.63-1.91; p < 0.001) had an association with an increased in-hospital mortality risk. CONCLUSION: AKI incidence was high among hospitalized older patients. Older patients with HA-AKI had worse in-hospital outcomes and higher resource utilization. Nephrotoxic drug exposure and HA-AKI incidence were associated with an increased in-hospital mortality risk.

Monocyte-to-lymphocyte ratio: a potential novel predictor for acute kidney injury in the intensive care unit.

Monocyte-to-lymphocyte ratio (MLR) and neutrophil-to-lymphocyte ratio (NLR) are considered as surrogate inflammatory indexes. Previous studies indicated that NLR was associated with the development of septic acute kidney injury (AKI). The objective of the present study was to explore the value of MLR and NLR in the occurrence of AKI in intensive care unit (ICU) patients. The clinical details of adult patients (n = 1500) who were admitted to the ICU from January 2016 to December 2019 were retrospectively examined. AKI was diagnosed according to the Kidney Disease: Improving Global Outcomes criteria. The development of AKI was the main outcome, and the secondary outcome was in-hospital mortality. Overall, 615 (41%) patients were diagnosed with AKI. Both MLR and NLR were positively correlated with AKI incidence (p < 0.001). Multivariate logistic regression analysis suggested that the risk value of MLR for the occurrence of AKI was nearly three-fold higher than NLR (OR = 3.904, 95% CI: 1.623‒9.391 vs. OR = 1.161, 95% CI: 1.135‒1.187, p < 0.001). The areas under the receiver operating characteristic curve (AUC) for MLR and NLR in the prediction of AKI incidence were 0.899 (95% CI: 0.881‒0.917) and 0.780 (95% CI: 0.755‒0.804) (all p < 0.001), with cutoff values of 0.693 and 12.4. However, the AUC of MLR and NLR in the prediction of in-hospital mortality was 0.583 (95% CI: 0.546‒0.620, p < 0.001) and 0.564 (95% CI: 0.528‒0.601, p = 0.001). MLR, an inexpensive and widely available parameter, is a reliable biomarker in predicting the occurrence of AKI in ICU patients.

Effect of forkhead box O1 in renal tubular epithelial cells on endotoxin-induced acute kidney injury.

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.

Receptor activator of NF-κB mediates podocyte injury in diabetic nephropathy.

Receptor activator of NF-κB (RANK) expression is increased in podocytes of patients with diabetic nephropathy. However, the relevance of RANK to diabetic nephropathy pathobiology remains unclear. Here, to evaluate the role of podocyte RANK in the development of diabetic nephropathy, we generated a mouse model of podocyte-specific RANK depletion (RANK-/-Cre T), and a model of podocyte-specific RANK overexpression (RANK TG), and induced diabetes in these mice with streptozotocin. We found that podocyte RANK depletion alleviated albuminuria, mesangial matrix expansion, and basement membrane thickening, while RANK overexpression aggravated these indices in streptozotocin-treated mice. Moreover, streptozotocin-triggered oxidative stress was increased in RANK overexpression but decreased in the RANK depleted mice. Particularly, the expression of NADPH oxidase 4, and its obligate partner, P22phox, were enhanced in RANK overexpression, but reduced in RANK depleted mice. In parallel, the transcription factor p65 was increased in the podocyte nuclei of RANK overexpressing mice but decreased in the RANK depleted mice. The relevant findings were largely replicated with high glucose-treated podocytes in vitro. Mechanistically, p65 could bind to the promoter regions of NADPH oxidase 4 and P22phox, and increased their respective gene promoter activity in podocytes, dependent on the levels of RANK. Taken together, these findings suggested that high glucose induced RANK in podocytes and caused the increase of NADPH oxidase 4 and P22phox via p65, possibly together with the cytokines TNF- α, MAC-2 and IL-1 ß, resulting in podocyte injury. Thus, we found that podocyte RANK was induced in the diabetic milieu and RANK mediated the development of diabetic nephropathy, likely by promoting glomerular oxidative stress and proinflammatory cytokine production.

Prospective model for predicting renal recovery in cardiac surgery patients with acute kidney injury requiring renal replacement therapy.

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 20 March 2012 and 9 August 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.

Is acute kidney injury age-dependent in older adults: an observational study in two centers from North China.

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.

Development and validation of a model for predicting acute kidney injury after cardiac surgery in patients of advanced age.

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.

Derivation and validation of a model to predict acute kidney injury following cardiac surgery in patients with normal renal function.

BACKGROUND: The study aimed to construct a clinical model based on preoperative data for predicting acute kidney injury (AKI) following cardiac surgery in patients with normal renal function. METHODS: A total of 22,348 consecutive patients with normal renal function undergoing cardiac surgery were enrolled. Among them, 15,701 were randomly selected for the training group and the remaining for the validation group. To develop a model visualized as a nomogram for predicting AKI, logistic regression was performed with variables selected using least absolute shrinkage and selection operator regression. The discrimination, calibration, and clinical value of the model were evaluated. RESULTS: The incidence of AKI was 25.2% in the training group. The new model consisted of nine preoperative variables, including age, male gender, left ventricular ejection fraction, hypertension, hemoglobin, uric acid, hypomagnesemia, and oral renin-angiotensin system inhibitor and non-steroidal anti-inflammatory drug within 1 week before surgery. The model had a good performance in the validation group. The discrimination was good with an area under the receiver operating characteristic curve of 0.740 (95% confidence interval, 0.726-0.753). The calibration plot indicated excellent agreement between the model prediction and actual observations. Decision curve analysis also showed that the model was clinically useful. CONCLUSIONS: The new model was constructed based on nine easily available preoperative clinical data characteristics for predicting AKI following cardiac surgery in patients with normal kidney function, which may help treatment decision-making, and rational utilization of medical resources.

The effect of amiloride in decreasing albuminuria in patients with diabetic kidney diseases: a prospective, crossover, open-label study.

BACKGROUND: Diabetic kidney diseases (DKD) were the leading cause of End-stage renal diseases worldwide. Albuminuria was a target for treatment in DKD and decreasing albuminuria was particularly important for improving its prognosis. However, there is still a lack of specific treatment for DKD. METHODS: We conducted a prospective, crossover, open-label study to investigate the effect of amiloride in patients with DKD. Safety and efficacy were assessed by monitoring urine protein creatinine ratio(uPCR), urinary albumin creatinine ratio (uACR), blood pressure, weight, serum sodium, serum potassium, cholesterol, triglyceride, uric acid, serum soluble urokinase-type plasminogen activator receptor (suPAR) and urinary suPAR. Ten subjects were enrolled in the trial. RESULTS: In this prospective, crossover, open-label design, amiloride could induce a significant decrease of uACR in DKD. The decrease of serum and urinary suPAR in the amiloride/hydrochlorothiazide (HCTZ) group was also significant compared with those patients using HCTZ as the control group. Correlation analysis showed that the levels of urinary suPAR were positively associated with uPCR and uACR. No significant difference in blood pressure, weight, serum sodium, serum potassium, cholesterol, triglyceride, uric acid was seen between the amiloride/HCTZ group and the control group. CONCLUSION: In summary, among patients with DKD, amiloride could decrease albuminuria without severe side effects, which was accompanied by the significant decline of urinary suPAR.

Response of mercury accumulation to anthropogenic pollution in the past 1000 years based on Lake Huguangyan sediments, Southern China.

A new 210Pb-dated record of Hg accumulation derived from a sediment core from a Hg-enriched area in Huguangyan Lake (HGY) in South China is presented. Based on synthetic analyses of multi-proxy records including chemical composition, total organic matter, and grain-size distribution in surface sediments and nearby soil samples, it is inferred that the influx of Hg into the lake is mainly a result of atmospheric deposition, with no or minor hydroclimate-induced lithogenic input from the catchment and limited adsorption effects of organic matter and clay. Significantly enhanced anthropogenic input of Hg started in the early 1900s. Since then, several anomalies of Hg accumulation have been the results of wars or intensified economic activities in China. HGY sediments provide a rare and reliable natural archive for detecting atmospheric Hg deposition, which is closely related to anthropogenic activities.

Histone deacetylase 4 mediates high glucose-induced podocyte apoptosis via upregulation of calcineurin.

Hyperglycemia promotes podocyte apoptosis and plays an important role in the pathogenesis of diabetic nephropathy (DN). Calcium/calcineurin (CaN) signaling is critical for podocyte apoptosis. Therefore, it is essential to elucidate the mechanisms underlying the regulation of CaN signaling. Recent studies reported that histone deacetylase 4 (HDAC4) is involved in podocyte apoptosis in DN. The aim of this study was to determine whether HDAC4 mediates the regulation of CaN and to elucidate the function of HDAC4 in high glucose (HG)-induced podocyte apoptosis. First, we identified the expression of HDAC4 was upregulated in podocytes of patients with DN. In vitro, the results also indicate that the mRNA and protein expression levels of HDAC4 were increased in HG-cultured podocytes. Silencing and overexpression of HDAC4 markedly decreased and increased CaN expression, respectively. Meanwhile, HG-induced podocyte apoptosis was abrogated by HDAC4-knockdown with subsequent decreased Bax expression and increased Bcl-2 expression. In contrast, overexpression of HDAC4 increased podocyte apoptosis and Bax expression, as well as decreased Bcl-2 expression. In addition, podocyte apoptosis induced by HDAC4 overexpression was effectively rescued by FK506, a pharmacological inhibitor of CaN, which was accompanied by decreased Bax and increased Bcl-2 expression. As a novel finding, HG-induced podocyte apoptosis is mediated by the HDAC4/CaN signaling pathway, which presents a promising target for therapeutic intervention in DN.

The Krüppel-like factor 15-NFATc1 axis ameliorates podocyte injury: a novel rationale for using glucocorticoids in proteinuria diseases.

Podocyte injury and loss contribute to proteinuria, glomerulosclerosis and eventually kidney failure. Recent studies have demonstrated that the loss of Kruppel-like factor 15 (KLF15) in podocytes increases the susceptibility to injury; however, the mechanism underlying the protective effects on podocyte injury remains incompletely understood. Herein, we showed that KLF15 ameliorates podocyte injury through suppressing NFAT signaling and the salutary effects of the synthetic glucocorticoid dexamethasone in podocyte were partially mediated by the KLF15-NFATc1 axis. We found that KLF15 was significantly reduced in glomerular cells of proteinuric patients and in ADR-, LPS- or HG-treated podocyets in vitro. Overexpression of KLF15 attenuated podocyte apoptosis induced by ADR, LPS or HG and resulted in decreased expression of pro-apoptotic Bax and increased expression of anti-apoptotic Bcl-2. Conversely, the flow cytometry analysis and TUNEl assay demonstrated that loss of KLF15 accelerated podocyte apoptosis and we further found that 11R-VIVIT, a specific NFAT inhibitor, and NFATc1-siRNA rescued KLF15-deficient induced podocyte apoptosis. Meanwhile, Western blot and RT-qPCR showed that the expression of NFATc1 was up-regulated in KLF15 silenced podocytes and reduced in KLF15 overexpressed podocytes. Mechanistically, ChIP analysis showed that KLF15 bound to the NFATc1 promoter region -1984 to -1861base pairs upstream of the transcription start site and the binding amount was decreased after treatment with LPS. The dual-luciferase reporter assay indicated that NFATc1 was a direct target of KLF15. In addition, we found that in vitro treatment with dexamethasone induced a decrease of NFATc1 expression in podocytes and was abrogated by knockdown of KLF15. Hence, our results identify the critical role of the KLF15-NFATc1 axis in podocyte injury and loss, which may be involved in mediating the salutary effects of dexamethasone in podocytes.

Effect of Dumbbell Exercise on Arteriovenous Fistula in Patients Undergoing Maintenance Haemodialysis: A Prospective Randomized Controlled Trial.

BACKGROUND: Arteriovenous fistulas (AVF) have been the main vascular accesses for haemodialysis patients, but the maintenance after maturation poses serious challenges. Arm exercises promote the maturation of AVFs. However, few studies have evaluated the effect of arm exercise on matured AVF and addressed the intervention for late fistula failure. OBJECTIVES: The study was conducted to explore the effect of dumbbell exercise on mature AVF. METHODS: 86 participants undergoing haemodialysis with AVFs were randomized into the control group and experimental group. The experimental group held 6-pound dumbbells on non-dialysis days for 3 months, while the control group squeezed rubber balls. RESULTS: For blood flow of draining vein (DV; primary outcome), the between-group effects, interaction effect and time effect showed significant differences. A significant increase in blood flow of DV was observed in the dumbbell group at the 3rd month (mean difference, 359.50 [111.90-829.05] mL/min; p = 0.001). The difference in blood flow of AVF proximal artery, blood flow of brachial artery, the diameter of DV and the incidence of adverse events at 3 months (secondary outcomes) between the 2 groups was insignificant. CONCLUSION: Prolonged training with arm exercises is essential for patients with AVFs though the fistula has matured. The designed dumbbell exercise is an economical, effective intervention to maintain the function of AVF, especially for patients with potential reduction of access blood flow and no percutaneous transluminal angioplasty indication.

Clinical value of renal phospholipase A2 receptor deposit in the prognosis evaluation and treatment options of idiopathic membranous nephropathy: A retrospective cohort study.

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.

The impact of coexisting diabetes mellitus on clinical outcomes in patients with idiopathic membranous nephropathy: a retrospective observational study.

BACKGROUND: Idiopathic membranous nephropathy (IMN) is frequently coexisted with diabetes mellitus (DM). Few researches investigate clinical outcomes in IMN patients coexisting diabetes mellitus (DM), including remission rates, renal survival and complications. Concurrent DM also pose therapeutic challenges to IMN patients due to the influence of glucocorticoids and immunosuppressant on metabolic disorders. We performed this study to investigate the impact of DM on clinical outcomes in IMN and the influence of therapeutic regime on metabolic parameters in diabetic IMN patients. METHODS: Two hundred and six adult hospitalized patients diagnosed with biopsy-proven IMN were retrospectively studied, including 42 patients coexisted with DM. Clinical outcomes including remission rates, renal outcome and complications were compared between groups. Impact of cyclophosphamide and ciclosporin on metabolism and complications were analyzed in IMN patients coexisting DM. RESULTS: IMN patients coexisted with DM were presented with advanced age, lower level of eGFR and hemoglobin. Patients coexisted with DM experienced worse renal function deterioration and higher incidence of infection. COX regression analysis showed that DM was an independent risk factor for renal function deterioration in IMN patients. There was no significant difference in remission rates and incidence of venous thromboembolism between two groups. Further exploration on the impact of therapeutic regimens on complications and metabolism showed that cyclophosphamide and ciclosporin had no significant difference in incidence of complications including infection and venous thromboembolism, and posed comparable influences on blood glucose, uric acid and blood lipids in IMN patients coexisted with DM. CONCLUSION: Coexisting DM was an independent risk factor for renal function deterioration in IMN patients but did not influence the remission of proteinuria. Glucocorticoids in combination with cyclophosphamide or ciclosporine had similar impact on complications and metabolic index including blood glucose, uric acid and blood lipids in IMN patients coexisted with DM.