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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.

The Qinghai–Tibet Plateau has given birth to many indigenous highland plants due to its special geographical location and sensitivity to climate change. Relevantly, the impact of climate change on species distribution has been a hot issue for research in biogeography. Using the maximum entropy (MaxEnt) model, the spatial distribution of habitat suitability for Fritillaria przewalskii Maxim. (FPM) on the Tibetan Plateau was predicted and ranked by combining ecological data and information on its actual current geographical distribution. The potential distribution and trends of FPM on the Tibetan Plateau from 2021 to 2040, 2041 to 2060, 2061 to 2080 and 2081 to 2100 under four current and future climate scenarios (SSP126, SSP245, SSP370 and SSP585) were also predicted. The predictions were found to be highly accurate with AUC values of 0.9645 and 0.9345 for the training and test sets, respectively. A number of conclusions could be drawn from the results. Firstly, the main ecological factors limiting the growth distribution of FPM were the Vegetation types, NPP (net primary production), Soil types, Bio7 (temperature annual range), Pop (population), Slope, GDP, Aspect, Bio1 (annual mean temperature) and Elevation, with a cumulative contribution of 97.6%. Secondly, in the recent past period of 1970–2000, the total suitable distribution area of FPM accounted for 5.55% of the plateau’s total area, which was about 14.11 × 104 km2, concentrated in its eastern and central regions. Thirdly, compared to the previous period, the aforementioned distribution area will, for the period spanning 2021–2040, increase by 14.48%, 16.23%, 16.99%, and 21.53% in the SSP126, SSP245, SSP370, and SSP585 scenarios, respectively. This comes with an overall expansion trend, and the areas predicted to be affected are concentrated in the eastern and central-western parts of the Tibetan Plateau. The other three future periods 2041–2060, 2061–2080, and 2081–2100 also show increases in these total areas to varying degrees. It is noteworthy that in the future periods 2061–2080 and 2081–2100, under the SSP370 and SSP585 scenarios, the area of high suitable distribution decreases or even disappears. Lastly, under the four climate scenarios, the FPM suitable distribution area will shift towards the western part of the Tibetan Plateau.

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.

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.

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.

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.

This paper aims to explore the lncRNA PROX1-AS1 effect on proliferation, migration, invasion, and apoptosis of lung cancer cells together with its targeted regulation on miR-1305. To adopt qRT-PCR to test PROX1-AS1 and miR-1305 expression levels in lung cancer tissues and adjacent tissues. Lung cancer cells A549 were cultured in vitro and randomly divided into several groups, which are si-NC, si-PROX1-AS1, miR-NC, miR-1305, si-PROX1-AS1 plus anti-miR-NC, and si-PROX1-AS1 plus anti-miR-1305. To adopt the CCK-8 method to test cell proliferation and to adopt the Transwell chamber experiment to test cell migration and invasion. To adopt the flow cytometry method to test the apoptosis rate. Through a dual luciferase experiment, we decided to find out the targeting relationship between PROX1-AS1 and miR-1305. Then we adopted the western blot method to test CyclinD1, MMP-2, MMP-9, Bcl-2, p21, and Bax expression levels. Compared with adjacent tissues ( P < 0.05 ), the expression of PROX1-AS1 in lung cancer tissue was remarkably higher, while the expression of miR-1305 was remarkably lower ( P < 0.05 ). After PROX1-AS1 knockdown expression or miR-1305 overexpression, cell activity, migration, and invasion ability were outstandingly lowered ( P < 0.05 ), but the apoptosis rate was obviously raised ( P < 0.05 ), CyclinD1, MMP-2, Bcl-2, and MMP-9 protein data were remarkably reduced ( P < 0.05 ), but p21 and Bax protein conditions were outstandingly enhanced ( P < 0.05 ). The dual luciferase experiment confirmed that PROX1-AS1 had a targeting relationship with miR-1305. After cotransfection with si-PROX1-AS1 and anti-miR-1305, the cell viability, migration and invasion ability were remarkably enhanced ( P < 0.05 ), the apoptosis rate was remarkably reduced ( P < 0.05 ), CyclinD1, MMP-2, Bcl-2, and MMP-9 protein were increased remarkably ( P < 0.05 ), and p21 or Bax protein was lowered remarkably ( P < 0.05 ). On the one hand, PROX1-AS1 can promote lung cancer proliferation, migration, and invasion. On the other hand, it may restrain apoptosis, possibly through inhibiting miR-1305 expression.

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.

BackgroundTreatments with glucocorticoids or immunosuppressants in IgA nephropathy remain controversial, especially in IgA nephropathy patients with renal insufficiency and small quantities of proteinuria. So far, no randomized controlled study has investigated whether cyclophosphamide has a protective effect on IgA nephropathy independent of glucocorticoids.MethodsWe conducted a single-center, randomized, controlled trial ((NCT01758120)). 135 IgA nephropathy patients with elevated plasma creatinine concentrations (1.3-3.0 mg/dl in males and 1.0-3.0 mg/dl in females), regardless of proteinuria level, were enrolled in and randomized 1:1 to the prednisone alone group or prednisone plus cyclophosphamide group. The daily dosage of oral prednisone was initiated at 0.5 mg/kg/d taken every morning for 2 months and then tapered by 20% each month for the next 4 months in prednisone alone group. In prednisone plus cyclophosphamide group cyclophosphamide was given in monthly pulses of 1.0 g for 6 months, while the prednisone dosage was the same as prednisone group. The two primary end points were a combination of reaching end-stage renal disease (ESRD) or doubling of serum creatinine or death and absolute changes in eGFR (estimated glomerular filtration rate) at 36 months.ResultsOverall, 135 patients were enrolled in our study. There was no significant difference between the two groups at baseline. The two groups had similar primary composite renal outcomes, which occurred in 4 participants (5.97%) in the prednisone alone group and 5 (7.35%) in the prednisone plus cyclophosphamide group (hazard ratio, 1.13 [95% CI, 0.30 to 4.19]; P = 0.861). Additionally, no significant difference in eGFR absolute change in three years was found between the two groups (0.09 (-7.42, 12.00) ml/min/1.73 m2 in the prednisone alone group vs. 3.24 (5.025, 9.59) ml/min/1.73 m2 in the prednisone plus cyclophosphamide group; P = 0.578). Proteinuria was reduced similarly in both groups. Treatment with cyclophosphamide led to more adverse events.ConclusionsOur study showed that corticosteroids plus cyclophosphamide did not increase the renal benefit of patients with advanced-stage IgA nephropathy but increased adverse effects compared with corticosteroids alone. Trial registration: ClinicalTrials.gov, NCT01758120. Registered 1 July 2012, https://clinicaltrials.gov/ct2/show/NCT01758120

Podocyte injury is sufficient to cause glomerulosclerosis and proteinuria, eventually leading to kidney failure. Previous studies found that podocytes and neurons had similar biological characteristics. Growth-associated protein-43 (GAP-43) is a growth cone protein in neurons, and a marker of axonal and synaptic growth. However, it is not known whether GAP-43 is expressed in podocytes. Compared with normal glomerular podocytes, GAP-43 was significantly reduced in patients with glomerular diseases. GAP-43 also significantly reduced in lipopolysaccharide (LPS)-treated podocytes. We found that the decreased expression of nephrin, the cell marker of the podocyte, was significantly recovered with GAP-43 overexpression. In contrast, the migration ability in LPS-treated podocyte was reduction after GAP-43 overexpressing. Moreover, overexpression of GAP-43 attenuated podocyte apoptosis by up-regulating the ratio of Bcl-2/Bax with LPS treatment. Finally, Plaue and Rcan1 which are downstream target gene of NFATc1 decreased with overexpression of GAP-43 podocytes. We concluded that GAP-43 attenuated podocyte injury by inhibiting calcineurin/NFATc1 signaling. The findings may provide a promising treatment for podocyte injury-related diseases., Highlights ● GAP-43 was expressed in glomeruli podocytes. ● GAP-43 was decreased in human podocytopathies and in LPS-treated podocytes. ● GAP-43 has anti-apoptotic effects on podocytes. ● GAP-43 ameliorated podocyte injury by suppressing calcineurin-NFATc1 signaling

Emotional memory deficit is often accompanied by Alzheimer's disease and normal aging. It is important to do what is possible to alleviate or rescue emotional memory deficit in aging to improve the quality of older adults. Hesperetin is a flavonoid and an aglycone of hesperidin, it easily passes through the blood-brain barrier into the brain and exerts neuroprotective effects. However, little is known about its neuroprotective effect on emotional memory in aging. To address this issue, we examined the role of hesperetin in the regulation of hippocampal long-term potentiation (LTP), surface expression of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) including glutamate receptor 1 subunit-containing AMPAR (GluA1) and glutamate receptor 1 subunit-containing AMPAR (GluA2), malondialdehyde (MDA) concentration, reduced glutathione (GSH) concentration, and associative fear memory in aged rats. We found that aged rats exhibited impaired emotional memory and LTP. Furthermore, we also found oral administration of hesperetin ameliorated the impairment of emotional memory and LTP. Finally, we demonstrated hesperetin rescued impaired LTP possibly via enhancing AMPAR trafficking and oxidant-antioxidant balance in aged rats. These results imply a pivotal role for hesperetin in synaptic plasticity and associative fear memory in aged rats and suggest that hesperetin is a potential candidate for treating emotional memory deficit in aging. (PsycInfo Database Record (c) 2021 APA, all rights reserved).

Autophagy is an important renal-protective mechanism in septic acute kidney injury (AKI). Receptor interacting protein kinase 3 (RIP3) has been implicated in the renal tubular injury and renal dysfunction during septic AKI. Here we investigated the role and mechanism of RIP3 on autophagy in septic AKI. We showed an activation of RIP3, accompanied by an accumulation of the autophagosome marker LC3II and the autophagic substrate p62, in the kidneys of lipopolysaccharide (LPS)-induced septic AKI mice and LPS-treated cultured renal proximal tubular epithelial cells (PTECs). The lysosome inhibitor did not further increase the levels of LCII or p62 in LPS-treated PTECs. Moreover, inhibition of RIP3 attenuated the aberrant accumulation of LC3II and p62 under LPS treatment in vivo and in vitro. By utilizing mCherry-GFP-LC3 autophagy reporter mice in vivo and PTECs overexpression mRFP-GFP-LC3 in vitro, we observed that inhibition of RIP3 restored the formation of autolysosomes and eliminated the accumulated autophagosomes under LPS treatment. These results indicated that RIP3 impaired autophagic degradation, contributing to the accumulation of autophagosomes. Mechanistically, the nuclear translocation of transcription factor EB (TFEB), a master regulator of the lysosome and autophagy pathway, was inhibited in LPS-induced mice and LPS-treated PTECs. Inhibition of RIP3 restored the nuclear translocation of TFEB in vivo and in vitro. Co-immunoprecipitation further showed an interaction of RIP3 and TFEB in LPS-treated PTECs. Also, the expression of LAMP1 and cathepsin B, two potential target genes of TFEB involved in lysosome function, were decreased under LPS treatment in vivo and in vitro, and this decrease was rescued by inhibiting RIP3. Finally, overexpression of TFEB restored the autophagic degradation in LPS-treated PTECs. Together, the present study has identified a pivotal role of RIP3 in suppressing autophagic degradation through impeding the TFEB-lysosome pathway in septic AKI, providing potential therapeutic targets for the prevention and treatment of septic AKI.

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.

Hypertension is one of the most common complications of chronic kidney disease (CKD). Some research has indicated that changes in large artery function especially caused by thromboxane A2 (TXA2) may be a novel factor acting to induce hypertension in CKD. We studied the 5/6 nephrectomy rat model and measured serum levels of creatinine (Cr), calcium (Ca), phosphorus (P), TXA2-stable metabolites (thromboxane B2, TXB2), and caudal artery pressure after nephrectomy. The tension variations in thoracic aortas were measured after stimulating by vasoconstrictor/vasodilator using the cumulative concentration administration method and then tested the expression of TXA2 receptors in the thoracic aortas through western blots. The CKD rats developed uremia, electrolyte imbalances，and hypertension. They also exhibited a significant increase in TXB2 concentration. The aortic rings of CKD rats showed an increased contraction response to U46619 (a TXA2 analogue) and the expression of TXA2 receptors also enhanced. In the meanwhile, the diastolic function decreased in the CKD group. Our results demonstrate that the impairment of artery contractile function caused by the increase of TXA2 receptors on the wall of aortic rings may be involved in hypertension in CKD rats.

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.

Background Noninvasive evaluation of hypoxia and fibrosis in kidney simultaneously by functional magnetic resonance imaging (MRI) to predict the prognosis of patients in prospective diabetic kidney disease (DKD) cohort has not been reported. We aim to assess the prediction value of blood oxygen level-dependent (BOLD) MRI and intravoxel incoherent motion (IVIM) diffusion-weighted image (DWI) in the prognosis of DKD.Methods 77 patients with diabetes mellitus (67 with DKD) were enrolled in this prospective cohort study in single center. BOLD-MRI and IVIM-DWI were used to assess renal hypoxia and fibrosis. A well-validated, reproducible method called twelve-layer concentric objects (TLCO) was applied to quantify the R2* values of BOLD (corresponds to oxygenation) and D values of IVIM (corresponds to fibrosis) derived from MRI. All patients received standard medical care according to guideline during study and followed up for 24.8 ± 12.6 months. The primary end points were serum creatinine (Scr) increasing > 30%, ERSD, or death.Results Our data demonstrated that medullary R2* value (MR2*) was significantly higher and cortical D value (CD) was markedly lower in DKD than those of diabetic controls, and strongly correlated with estimated glomerular filtration rate. Both the higher MR2* (log-rank test, P P Conclusions Integrating BOLD-MRI and IVIM-DWI quantified by TLCO was more efficient than each single of them in assessment of renal outcomes; thus, could be a noninvasive tool to predict the prognosis of DKD.Trial registration The study protocol was registered at the Chinese Clinical Trial Registry Center (NO: ChiCTR-RRC-17012687; date of registration: 16/09/2017).

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.