The Role for AVE0991 (MAS-Receptor Angiotensin II (1-7) Agonist) in Reducing Cisplatin-Induced Acute Kidney Injury on C57BL/6 Mice

Acute Kidney Injury (AKI) is a condition that causes nephrotoxicity in kidney tissues due to cisplatin-induced cancer treatments. Hence, it is proposed in this review that AVE0991 (a MAS-receptor Angiotensin II (1-7) agonist) may reduce cisplatin-induced acute kidney injury by promoting nitric oxide production.

Mechanism of miR-214-mediated HIF1 α and KIM1 signaling pathway in rats with ischemic acute kidney injury

Objective:To investigate the mechanism of mir-214-mediated HIF1 alpha and KIM1 signaling pathways in rats with ischemic acute kidney injury. Methods:Rats were divided into three groups according to the difference of the preparation model, 16 in each group, sham operation group, IAKI group and miR-214 group.The rats in the latter two groups were established with ischemic acute kidney injury. After 48 hours, three groups of rats were treated with orbital venous blood. Urine was collected, biochemical parameters and KIM1 expression were detected. After using Masson's Trichrome, TUNEL, immunoblotting and PCR, renal histopathology, apoptosis of glomerular epithelial cells and expression of HIF1α, KIM1 protein and mRNA in renal tissues were detected. Results:The biochemical parameters of rats in the IAKI group included Scr, BUN and 24hUTP, which were higher than the previous group (P<0.05). The MIR-214 group was higher than the IAKI group. The sham operation group had intact renal tissue structure and good renal tubular and glomeruli. The IAKIgroup had increased glomerular interstitial, renal interstitial widening and inflammation. Severe infiltration, severe tubular atrophy, miR-214 group and IAKIgroup, renal interstitial inflammation increased, hardness increased, tubular atrophy more serious;black yellow is apoptotic cells, IAKIgroup rat renal tubular epithelial cell apoptosis The most serious, the degree of apoptosis was significantly higher than the sham operation group;the degree of apoptosis of renal tubular epithelial cells was increased in the miR-214 group compared with the IAKIgroup, and high levels of miR-214 could accelerate the apoptosis of epithelial cellsThe HIF1α and KIM1 proteins in the IAKI group were higher than those in the Previous group(P<0.05). The above indexes in the mir-214 group were better than those in the IAKI group(P<0.05). The HIF1α and KIM1 mRNA in the IAKI group were higher than in the sham operation group, and the above indicators in the mir-214 group(P<0.05). Better than the IAKI group(P<0.05);Conclusions:The increase of miR-214 accelerates the apoptosis of glomerular epithelial cells, impaired renal tissue damage, and mediates the elevation of HIF1α and KIM1, further aggravating the condition of IAKI rats.

Ginsenoside Rg1 and Resveratrol Alleviate Acute Kidney Injury Induced by Cisplatin via Downregulation of Autophagy in Mice

Background: Cisplatin, a chemotherapeutic agent, is widely used in the treatment of malignant tumors. Nephrotoxicity, especially acute kidney injury (AKI), is the most common and severe adverse reaction of cisplatin. Resveratrol and ginsenoside Rg1, two natural products, have been found to have renal protective effects. However, the effects and the mechanisms in cisplatin-induced AKI need further investigation. Methods: The mouse models of cisplatin-induced AKI and several treatment groups were established. Male C57BL/6 mice were divided into five groups: saline control group, cisplatin injury group, resveratrol treatment group, Rg1 treatment group, resveratrol and Rg1 combined treatment group. Serological analysis of serum urea nitrogen was aimed to reflect the function of kidney, and histological analysis of renal tissue sections was aimed to assess the damage of proximal convoluted tubules. The expression levels of autophagy-related proteins Beclin 1 and LC3 were detected by western blotting and qRT-PCR respectively. Results: The renal function was improved and renal damage was alleviated in Rg1 and resveratrol alone or combined treatment groups compared with the cisplatin injury group. For the mechanism, treatment with Rg1 and resveratrol alone or in combination decreased the expressions of Beclin 1 both at protein and mRNA levels, decreased LC3II/I protein levels, indicating that autophagy was inhibited by treatment with Rg1 and resveratrol alone or in combination. Conclusion: Resveratrol and Rg1 alleviated the kidney damage caused by cisplatin, and reduced autophagy was involved in the renoprotective effects of resveratrol and Rg1 against cisplatin-induced AKI. This study may provide new evidence to alleviate cisplatin-induced AKI.

Neutrophil gelatinase-associated lipocalin does not predict acute kidney injury in heart failure

BACKGROUND Acute cardiorenal syndrome type 1(CRS-1)is defined by a rapid cardiac dysfunction leading to acute kidney injury(AKI).Neutrophil gelatinaseassociated lipocalin(NGAL)is expressed on the surface of human neutrophils and epithelial cells,such as renal tubule cells,and its serum(sNGAL)and urinary have been used to predict AKI in different clinical settings.AIM To characterize CRS-1 in a cohort of patients with acute heart diseases,evaluating the potentiality of sNGAL as an early marker of CRS-1.METHODS We performed a retrospective cohort,multi-centre study.From January 2010 to December 2011,we recruited 202 adult patients admitted to the coronary intensive care unit(CICU)with a diagnosis of acute heart failure or acute coronary syndrome.We monitored the renal function to evaluate CRS-1 development and measured sNGAL levels within 24 h and after 72 h of CICU admission.RESULTS Overall,enrolled patients were hemodynamically stable with a mean arterial pressure of 92(82-107)mmHg,55/202(27.2%)of the patients developed CRS-1,but none of them required dialysis.Neither the NGAL delta value(AUC 0.40,95%CI:0.25-0.55)nor the NGAL peak(AUC 0.45,95%CI:0.36-0.54)or NGAL cutoff(≥140 ng/mL)values were statistically significant between the two groups(CRS-1 vs no-CRS1 patients).The area under the ROC curve for the prediction of CRS-1 was 0.40(95%CI:0.25-0.55)for the delta NGAL value and 0.45(95%CI:0.36-0.54)for the NGAL peak value.Finally,in multivariate analysis,the risk of developing CRS-1 was correlated with age>60 years,urea nitrogen at admission and 24 h-urine output(AUC 0.83,SE=60.5%SP=93%),while sNGAL was not significantly correlated.CONCLUSION In our population,sNGAL does not predict CRS-1,probably as a consequence of the mild renal injury and the low severity of heart disease.So,these data might suggest that patient selection should be taken into account when considering the utility of NGAL measurement as a biomarker of kidney damage.

Urine microscopy and neutrophilelymphocyte ratio are early predictors of acute kidney injury in patients with urinary tract infection

Objective:Urinary tract infection(UTI)is a common cause of morbidity and hospitalisation in the population worldwide.Upper UTI is indolent and causes subclinical acute kidney injury(AKI)resulting in preventable cause of scarring of renal parenchyma.We explored urinary and serum levels of kidney injury molecule-1(KIM-1),haematological parameters and quantitative urine microscopy parameters to predict kidney injury.Methods:Neutrophilelymphocyte ratio(NLR)is obtained by dividing absolute neutrophil count with absolute lymphocyte count.Quantitative urine sediment microscopy was performed and correlated with clinical,biochemical and haematological findings to predict AKI in patients with UTI.Quantitative ELISA was performed for serum and urine levels of KIM-1.Seventy two adult patients with UTI were enrolled,45 of whom had AKI while 27 were in the non-AKI group.Results:NLR(p=0.005)and renal tubular epithelial cell-granular cast score in quantitative urine microscopy(p=0.008)are strong predictors of AKI in patients with UTI while rest of quantitative urine microscopy parameters and serum and urinary levels of KIM-1 molecule were not found to be useful in prediction of AKI.Conclusion:NLR in haemogram is a novel and useful biomarker for predicting AKI in patients with UTI.

TOPK Activation Exerts Protective Effects on Cisplatin-induced Acute Kidney Injury

Objective:T-LAK-cell-originated protein kinase(TOPK),a PSD95-Disc large-ZO1(PDZ)binding kinase(PBK),is a novel member of the mitogen-activated protein kinase(MAPK)family.Studies have shown that TOPK plays a critical role in the function of tumor cells,including apoptosis and mitosis.However,little is known on the effect of TOPK in cisplatin-induced acute kidney injury(CP-AKI).This study aimed to investigate the role and mechanism of TOPK in CPAKI.Methods:Cisplatin was administered to C57BL/6 mice and cultured kidney tubular epithelial cells(TECs)to establish the CP-AKI murine or cellular models.TECs were then stimulated with the specific inhibitor of TOPK OTS514 or transfected with the recombinant-activated plasmid TOPK-T9E to inhibit or activate TOPK.The TECs were treated with AKT inhibitorⅧfollowing stimulation with OTS514 or cisplatin.Western blotting and flow cytometry were used to evaluate the cell cycle and apoptosis of TECs.Results:The analysis revealed that the TOPK activity was significantly suppressed by cisplatin,both in vivo and in vitro.Furthermore,the pharmacological inhibition of TOPK by OTS514,a specific inhibitor of TOPK,exacerbated the cisplatin-induced cell cycle arrest in the G2/M phase and apoptosis of cultured TECs.Moreover,the TOPK activation via the TOPK-T9E plasmid transfection could partially reverse the cell cycle arrest at the G2/M phase and apoptosis of cisplatin-treated TECs.In addition,AKT/protein kinase B(PKB),as a TOPK target protein,was inhibited by cisplatin in cultured TECs.The pharmaceutical inhibition of AKT further aggravated the apoptosis of TECs induced by cisplatin or TOPK inhibition.TOPK systematically mediated the apoptosis via the AKT pathway in the CP-AKI cell model.Conclusion:These results indicate that TOPK activation protects against CP-AKI by ameliorating the G2/M cell cycle arrest and cell apoptosis.

Levetiracetam-Associated Acute Kidney Injury and Drug Reaction with Eosinophilia and Systemic Symptoms (DRESS) Syndrome

DRESS syndrome is a severe drug induced reaction. Acute kidney injury (AKI) is sometimes present in the form of an acute interstitial nephritis. We present the case of a 75-year-old man with glioblastoma who developed a DRESS two months after starting levetiracetam and a few days after stopping dexamethasone. His skin and kidneys improved after removing levetiracetam and introducing again corticosteroids. DRESS has been reported more frequently with other antiepileptics, rarely with levetiracetam. Clinicians should add this drug to the list of potential causes of AKI.

MicroRNA-30a inhibits cell proliferation in a sepsis-induced acute kidney injury model by targeting the YAP-TEAD complex

Background Acute kidney injury(AKI)is a primary feature of renal complications in patients with sepsis.MicroRNA(miRNA/miR)-30a is an essential regulator of cardiovascular diseases,tumors,phagocytosis,and other physical processes,but whether it participates in sepsis-induced AKI(sepsis-AKI)is unknown.We aimed to elucidate the functions and molecular mechanism underlying miR-30a activity in sepsis-AKI.Methods The classical cecal ligation and puncture(CLP)method and lipopolysaccharide(LPS)-induced Human Kidney 2(HK-2)cells were used to establish in vivo and in vitro sepsis-AKI models.Specific pathogen-free and mature male Sprague-Dawley(SD)rats,aged 6–8 weeks(weight 200–250 g),were randomly divided into five-time phase subgroups.Fluid resuscitation with 30 mL/kg 37°C saline was administered after the operation,without antibiotics.Formalin-fixed,paraffin-embedded kidney sections were stained with hematoxylin and eosin.SD rat kidney tissue samples were collected for analysis by real-time quantitative polymerase chain reaction and enzyme-linked immunosorbent assay.HK-2 cells were transfected with hsa-miR-30a-3p mimics or inhibitors,and compared with untreated normal controls.RNA,protein,and cell viability were evaluated by quantitative reverse transcription-polymerase chain reaction(qRT-PCR),western blot,and cell counting kit-8 methods.A Dual-Luciferase Assay Kit(Promega)was used to measure luciferase activity 48 h after transfection with miR-30a-3p mimics.Results Expression levels of miR-30a-3p and miR-30a-5p in renal tissues of the sepsis group were significantly reduced at 12 h and 24 h(P<0.05).Tumor necrosis factor-α(TNF-α)and interleukin-1β(IL-1β)were significantly increased in renal tissue 3 h after the operation in rats(P<0.05),and gradually decreased 6 h,12 h,and 24 h after CLP.Levels of miR-30a-5p and miR-30a-3p were significantly down-regulated at 3 h after LPS treatment(P<0.05),and gradually decreased in HK-2 cells.One hour after LPS(10µg/mL)treatment,TNF-αand IL-1βlevels in HK-2 cells were significantly up-regulated(P<0.05),and they were markedly down-regulated after 3 h(P<0.05).IL-6 expression levels began to rise after LPS treatment of cells,peaked at 6 h(P<0.05),and then decreased to the initial level within a few hours.Stimulation with 10µg/mL LPS promoted HK-2 cells proliferation,which was inhibited after miR-30a-3p-mimic transfection.Bioinformatics prediction identified 37 potential miR-30a-3p target genes,including transcriptional enhanced associate domain 1(TEAD1).After transfection of HK-2 cells with miR-30a-3p mimics and miR-30a-3p inhibitor,TEAD1 transcript was significantly up-and down-regulated,respectively(both P<0.05).After LPS treatment(24 h),expression of TEAD1 in the inhibitors group was significantly increased(P<0.01),while that in the mimics group was significantly suppressed(P<0.01).In the dual luciferase reporter experiment,miR-30a-3p overexpression decreased fluorescence intensity(P<0.01)from TEAD1-wt-containing plasmids,but did not influence fluorescence intensity from TEAD1-muta-containing plasmids.LPS may promote HK-2 cells proliferation through the miR-30a-3p/TEAD1 pathway.Conclusion In a background of expression of inflammatory factors,including TNF-α,IL-1β,and IL-6,which were transiently increased in the sepsis-AKI model,miR-30a was down-regulated.Down-regulated miR-30a-3p may promote cell proliferation by targeting TEAD1 in LPS-induced HK-2 cells,demonstrating its potential as a biomarker for early sepsis-AKI diagnosis.

Urinary Kidney Injury Molocule-1 Level in Preterm Neonates with Respiratory Distress Syndrome

Background: Despite recent advances in perinatal and neonatal care in respiratory distress syndrome (RDS) prevention and treatment, a considerable number of these neonates suffer from acute kidney injury (AKI), and it is associated with poor outcome as an independent risk factor. KIM-1 mRNA and protein are expressed at a low level in normal kidney but are increased in post ischemic kidney. Aim: The aim is to detect the value of urinary KIM-1 measurement as an early predictor marker of acute kidney injury in preterm neonates with respiratory distress syndrome. Patients and methods: The study included 30 preterm newborn with (RDS) ≤36 weeks during the period from October 2014 to March 2015. Also the study included 30 apparently healthy newborn ≤36 weeks as controls. They were selected from NICU of Manshiate Elbakry hospital Cairo, Egypt. uKIM-1 along with serum creatinine levels and eGFR were assessed in days 1 of life for both groups and in day 3 for cases. Results: In day one of life, we found a significant increase in uKIM-1 levels in preterm newborn with RDS compared to their controls (2.88 ± 1.01 ng/ml and 0.95 ± 0.52 ng/ml respectively (p = 0.001)). There is no significant difference between both groups regarding serum creatinine and eGFR. In day 3 of life, preterm with RDS had significant decrease in uKIM-1 levels compared to day 1 of life with significant increase in non-survivor compared to survivor group ( 2.30 ± 1.56 ng/ml and 1.30 ± 0.90 ng/ml respectively (p = 0.03)). The sensitivity and specificity of uKIM-1 and serum creatinine was calculated (100.00%, 86.67% and 33.33%;95.00%) respectively. Conclusion: Preterm neonate with RDS is at high risk of developing AKI. Early and serial uKIM-1 measurements can be used as a non-invasive indicator of kidney injury in premature newborn with RDS.

CD36 promotes tubular ferroptosis by regulating the ubiquitination of FSP1 in acute kidney injury

Reactive oxidative species(ROos)production-driven ferroptosis plays a role in acute kidney injury(Akl).However,its exact molecular mechanism is poorly understood.Scavenger receptor CD36 has important roles in oxidizing lipids,lipid accumulation,metabolic syndrome,and insulin resistance in chronic kidney disease,but its roles remain unexplored in AKl.The present study investigated the role and mechanism of CD36 in regulating proximal tubular cell ferroptosis and AKl.The expression of CD36 was found to be significantly up-regulated in AKI renal tissues and correlated with renal function,which might serve as an independent biomarker for AKl patients.Moreover,in adult mice subjected to AKl,deletion of CD36(CD36-/-)induced tubular cell Ros accumulation,ferroptosis activation,and renal injury.Mechanistically,combining LC-MS/MS,co-IP,and ubiquitination analyses revealed that CD36 could specifically bind to ferroptosis suppressor protein 1(FSP1)and regulate its ubiquitination at sites K16 and K24,leading to FSP1 degradation and progression of ferroptosis in AKl.The present results emphasize a novel mechanism of CD36 in cisplatin-induced AKl.The discovery of the special CD36 roles in promoting ferroptosis and AKI development by regulating the ubiquitination of FSP1 in proximal tubular cells may be potential therapeutic targets for AKl.Moreover,CD36 may play a key role in the progression of AKl.Therefore,targeting CD36 may provide a promising treatment option for AKI.

A novel marine-derived anti-acute kidney injury agent targeting peroxiredoxin 1 and its nanodelivery strategy based on ADME optimization

Insufficient therapeutic strategies for acute kidney injury(AKI)necessitate precision therapy targeting its pathogenesis.This study reveals the new mechanism of the marine-derived anti-AKI agent,piericidin glycoside S14,targeting peroxiredoxin 1(PRDX1).By binding to Cys83 of PRDX1 and augmenting its peroxidase activity,S14 alleviates kidney injury efficiently in Prdx1-overexpression(Prdx1-OE)mice.Besides,S14 also increases PRDX1 nuclear translocation and directly activates the Nrf2/HO-1/NQO1 pathway to inhibit ROS production.Due to the limited druggability of S14 with low bioavailability(2.6%)and poor renal distribution,a pH-sensitive kidney-targeting dodecanaminechitosan nanoparticle system is constructed to load S14 for precise treatment of AKI.L-Serine conjugation to chitosan imparts specificity to kidney injury molecule-1(Kim-1)-overexpressed cells.The developed S14-nanodrug exhibits higher therapeutic efficiency by improving the in vivo behavior of S14 significantly.By encapsulation with micelles,the AUC_(0-t),half-life time,and renal distribution of S14 increase 2.5-,1.8-,and 3.1-fold,respectively.The main factors contributing to the improved druggability of S14 nanodrugs include the lower metabolic elimination rate and UDPglycosyltransferase(UGT)-mediated biotransformation.In summary,this study identifies a new therapeutic target for the marine-derived anti-AKI agent while enhancing its ADME properties and druggability through nanotechnology,thereby driving advancements in marine drug development for AKI.

Red blood cell distribution width improves the prediction of 28-daymortality for patients with sepsis-induced acute kidney injury:A retrospective analysis from MIMIC-IV database usingpropensity score matching

Background:The predictive value of red blood cell distribution width(RDW)for mortality in patients withsepsis-induced acute kidney injury(SI-AKI)remains unclear.The present study aimed to investigate the potentialassociation between RDW at admission and outcomes in patients with SI-AKI.Methods:The Medical Information Mart for Intensive Care(MIMIC)-IV(version 2.0)database,released in Juneof 2022,provides medical data of SI-AKI patients to conduct our related research.Based on propensity scorematching(PSM)method,the main risk factors associated with mortality in SI-AKI were evaluated using Coxproportional hazards regression analysis to construct a predictive nomogram.The concordance index(C-index)and decision curve analysis were used to validate the predictive ability and clinical utility of this model.Patientswith SI-AKI were classified into the high-and low-RDW groups according to the best cut-off value obtained bycalculating the maximum value of the Youden index.Results:A total of 7574 patients with SI-AKI were identified according to the filter criteria.Compared withthe low-RDW group,the high-RDW group had higher 28-day(9.49%vs.31.40%,respectively,P<0.001)and7-day(3.96%vs.13.93%,respectively,P<0.001)mortality rates.Patients in the high-RDW group were moreprone to AKI progression than those in the low-RDW group(20.80%vs.13.60%,respectively,P<0.001).Basedon matched patients,we developed a nomogram model that included age,white blood cells,RDW,combinedhypertension and presence of a malignant tumor,treatment with vasopressor,dialysis,and invasive ventilation,sequential organ failure assessment,and AKI stages.The C-index for predicting the probability of 28-day survivalwas 0.799.Decision curve analysis revealed that the model with RDW offered greater net benefit than that withoutRDW.Conclusion:The present findings demonstrated the importance of RDW,which improved the predictive ability ofthe nomogram model for the probability of survival in patients with SI-AKI.

Prognostic Factors in Cardiorenal Syndrome Type 1: Retrospective Observational and Analytical Study

Introduction: Type 1 cardiorenal syndrome (CRS 1) is characterized by acute impairment of cardiac function leading to acute renal dysfunction. CRS1 is present in 25% of patients admitted for heart failure. The objective of our study is to analyze the epidemiological, clinical, therapeutic profile and the risk and prognostic factors of these patients. Materials and Methods: We identified 120 patients with cardiorenal syndrome (CRS) over a one-year period to determine the prevalence and risk factors for developing CRS 1. We analyzed the clinical, biological, and evolutionary profiles of patients with CRS 1 and determined the risk factors for the occurrence of acute kidney injury (AKI) as well as the mortality factors in these patients. Résultats: The average age of our patients with CRS1 is 58 ± 9 years, with a sex ratio of 1.4. The average eGFR of our patients is 35 ± 6.5 ml/min/1.73m2. Diabetes was found in 17% of our patients and hypertension in 14%. The etiology of cardiac impairment is predominantly acute coronary syndrome (ACS), followed by rhythm disorders. Renally, all our patients have acute kidney injury (AKI), with 86% having functional acute renal failure and 14% having acute tubular necrosis. Therapeutically, 50% of our patients are on diuretics, 42% receive beta-blocker treatment, and RAAS blockers are used in 29% of cases. Renal replacement therapy (RRT) sessions were required in 13.8% of cases. In univariate analysis, male gender, tachyarrhythmia, and hypertension are associated with the early onset of acute kidney injury (AKI). The use of diuretics, anemia, and low left ventricular ejection fraction (LVEF) are linked to a higher risk of developing CRS 1 (p = 0.021, p = 0.037, p = 0.010 respectively). In multivariate analysis, advanced age is significantly associated with increased mortality risk in CRS 1 patients (p = 0.030), while beta-blocker use is considered a protective factor (p = 0.014). Conclusion: Our study identifies several key factors associated with outcomes in type 1 CRS. Male gender, tachyarrhythmia, and hypertension are linked to early-onset AKI. The use of diuretics and the presence of anemia increase the risk of developing CRS1. Advanced age is significantly associated with higher mortality rates. Conversely, the use of beta-blockers appears to be protective in this patient population. .

Involvement of phosphatase and tensin homolog-induced putative kinase 1–Parkin-mediated mitophagy in septic acute kidney injury

Background:Studies have reported mitophagy activation in renal tubular epithelial cells(RTECs)in acute kidney injury(AKI).Phosphatase and tensin homolog-induced putative kinase 1(PINK1)and E3 ubiquitin-protein ligase Parkin are involved in mitophagy regulation;however,little is known about the role of PINK1-Parkin mitophagy in septic AKI.Here we investigated whether the PINK1-Parkin mitophagy pathway is involved in septic AKI and its effects on cell apoptosis in vitro and on renal functions in vivo.Methods:Mitophagy-related gene expression was determined using Western blot assay in human RTEC cell line HK-2 stimulated with bacterial lipopolysaccharide(LPS)and in RTECs from septic AKI rats induced by cecal ligation and perforation(CLP).Autophagy-related ultrastructural features in rat RTECs were observed using electron microscopy.Gain-and loss-of-function approaches were performed to investigate the role of the PINK1-Parkin pathway in HK-2 cell mitophagy.Autophagy activators and inhibitors were used to assess the effects of mitophagy modulation on cell apoptosis in vitro and on renal functions in vivo.Results:LPS stimulation could significantly induce LC3-II and BECN-1 protein expression(LC3-II:1.72±0.05 vs.1.00±0.05,P<0.05;BECN-1:5.33±0.57 vs.1.00±0.14,P<0.05)at 4 h in vitro.Similarly,LC3-II,and BECN-1 protein levels were significantly increased and peaked at 2 h after CLP(LC3-II:3.33±0.12 vs.1.03±0.15,P<0.05;BECN-1:1.57±0.26 vs.1.02±0.11,P<0.05)in vivo compared with those after sham operation.Mitochondrial deformation and mitolysosome-mediated mitochondria clearance were observed in RTECs from septic rats.PINK1 knockdown significantly attenuated LC3-II protein expression(1.35±0.21 vs.2.38±0.22,P<0.05),whereas PINK1 overexpression markedly enhanced LC3-II protein expression(2.07±0.21 vs.1.29±0.19,P<0.05)compared with LPS-stimulated HK-2 cells.LPS-induced proapoptotic protein expression remained unchanged in autophagy activator-treated HK-2 cells and was significantly attenuated in PINK1-overexpressing cells,but was remarkably upregulated in autophagy inhibitor-treated and in PINK1-depleted cells.Consistent results were observed in flow cytometric apoptosis assay and in renal function indicators in rats.Conclusion:PINK1-Parkin-mediated mitophagy might play a protective role in septic AKI,serving as a potential therapeutic target for septic AKI.

Resolvin D1 Protects Lipopolysaccharide-induced Acute Kidney Injury by Down-regulating Nuclear Factor-kappa B Signal and Inhibiting Apoptosis

Background： Resolvin D1 （RvD1） is a newly found anti-inflammatory bioactive compound derived from polyunsaturated fatty acids. The current study aimed to explore the protective effect of RvD1 on lipopolysaccharide （LPS）-induced acute kidney injury （AKI） and its possible mechanism. Methods： Both in vivo and in vitro studies were conducted. Male BALB/c mice were randomly divided into control group （saline）, LPS group （LPS 5 mg/kg）, RvD1 group （RvD1 5 μg/kg ＋ LPS 5 mg/kg）, and blockage group （Boc-MLP 5 gg/kg ＋ RvD1 5 gg/kg ＋ LPS 5 mg/kg）. Boc-MLP is a RvD 1 receptor blocker. The mice were intraperitoneally injected with these drugs and recorded for general condition for 48 h, while the blood and kidneys were harvested at 2, 6, 12, 24, and 48 h time points, respectively （n = 6 in each group at each time point）. Human proximal tubule epithelial cells （HK-2） were randomly divided into control group （medium only）, LPS group （LPS 5 μg/ml）, RvD1 group （RvD1 10 ng/ml ＋ LPS 5 μg/ml）, and blockage group （Boc-MLP 10 ng/ml ＋ RvD1 10 ng/ml ＋ LPS 5 μg/ml）. The cells were harvested for RNA at 2, 4, 6, 12, and 24 h time points, respectively （n = 6 in each group at each time point）. Blood creatinine was tested by using an Abbott i-STAT portable blood gas analyzer. Tumor necrosis factor-α （TNF-α level was detected by EL1SA. Kidney pathology was observed under hematoxylin and eosin （HE） staining and transmission electron microscope （TEM）. We hired immune-histological staining, Western blotting, and fluorescence quantitative polymerase chain reaction to detect the expression of RvD1 receptor ALX, nuclear factor-kappa B （NF-KB） signaling pathway as well as caspase-3. Kidney apoptosis was evaluated by TUNEL staining. Results： RvD 1 receptor ALX was detected on renal tubular epithelials. Kaplan-Meier analysis indicated that RvD 1 improved 48 h animal survival （80%） compared with LPS group （40%） and RvDI blockage group （60%）, while RvD1 also ameliorated kidney pathological injury in HE staining and TEM scan. After LPS stimulation, the mRNA expression of toll-like receptor 4, myeloid differentiation factor 88, and TNF-α in both mice kidneys and HK-2 cells were all up-regulated, while RvDI substantially inhibited the up-regulation of these genes. Western blotting showed that the phosphorylated-IKB/IKB ratio in LPS group was significantly higher than that in the control group, which was inhibited in the RvD1 group. RvD1 could inhibit the up-regulation of cleaved-caspase-3 protein stimulated by LPS, which was prohibited in RvD 1 blockage group. RvD 1 group also had a lower proportion of apoptotic nuclei in mice kidney by TUNEL staining compared with LPS group. Conclusion： In LPS-induced AKI, RvD1 could decrease TNF-α level, ameliorate kidney pathological injury, protect kidney function, and improve animal survival by down-regulating NF-KB inflammatory signal as well as inhibiting renal cell apoptosis.

Value of urine IL-8, NGAL and KIM-1 for the early diagnosis of acute kidney injury in patients with ureteroscopic lithotripsy related urosepsis

Purpose::To investigate the clinical value of urine interleukin-18(IL-8),neutrophil gelatinase-associated lipocalin(NGAL)and kidney injury molecule-1(KIM-1)for the early diagnosis of acute kidney injury(AKI)in patients with ureteroscopic lithotripsy(URL)related urosepsis.Methods::A retrospective study was carried out in 157 patients with urosepsis after URL.The patients were divided into AKI group and non-AKI group according to the Kidigo guideline and urine IL-8,NGAL and KIM-1 levels were detected by enzyme-linked immunosorbent assay at 0,4,12,24 and 48 h after the surgery.Receiver operating characteristic curve(ROC)was used to evaluate the diagnostic value of these three biomarkers for postoperative AKI.Results::The level of urine IL-8,NGAL and KIM-1 in AKI group was significantly higher than that in non-AKI group at 4,12,24 and 48 h(p<0.01).The ROC analysis showed the combined detection of urine IL-8,NGAL and KIM-1 at 12 h had a larger area under curve(AUC)than a single marker(0.997,95%CI:0.991-0.998),and the sensitivity and specificity were 98.2%and 96.7%,respectively.Pearson correlation analysis showed that the levels of urine NGAL at 4,12,24 and 48 h in AKI patients were positively correlated with the levels of urine KIM-1 and IL-18(p<0.01).Conclusion::AKI could be quickly recognized by the elevated level of urine IL-8,NGAL and KIM-1 in patients with URL-related urosepsis.Combined detection of the three urine biomarkers at 12 h after surgery had a better diagnostic performance,which may be an important reference for the early diagnosis of AKI.

The duration of acute kidney injury is an additional parameter to predict1-year survival in very elderly patients

Background:Acute kidney injury(AKI)is primarily defined and classified according to the magnitude of theelevation of serum creatinine(Scr).We aimed to determine whether the duration of AKI adds prognostic valuein addition to that obtained from the magnitude of injury alone.Methods:This retrospective study enrolled very elderly inpatients(≥75 years)in the Chinese PLA General Hospitalfrom January 2007 to December 2018.AKI was stratified by magnitude according to KDIGO stage(1,2,and 3)andduration(1–2 days,3–4 days,5–7 days,and>7 days).The primary outcome was the 1-year mortality after AKI.Multivariable Cox regression analysis was performed to identify covariates associated with the 1-year mortality.The probability of survival was estimated using the Kaplan–Meier method,and curves were compared using thelog-rank test.Results:In total,688 patients were enrolled,with the median age was 88(84–91)years,and the majority(652,94.8%)were male.According to the KDIGO criteria,317 patients(46.1%)had Stage 1 AKI,169(24.6%)hadStage 2 AKI,and 202(29.3%)had Stage 3 AKI.Of the 688 study subjects,61(8.9%)with a duration of AKIlasted 1–2 days,104(15.1%)with a duration of AKI lasted 3–4 days,140(20.3%)with a duration of AKI lasted5–7 days,and 383(55.7%)with a duration of AKI lasted>7 days.Within each stage,a longer duration of AKIwas slightly associated with a higher rate of 1-year mortality.However,within each of the duration categories,the stage of AKI was significantly associated with 1-year mortality.When considered separately in multivariateanalyses,both the duration of AKI(3–4 days:HR=3.184;95%CI:1.733–5.853;P<0.001,5–7 days:HR=1.915;95%CI:1.073–3.416;P=0.028;>7 days:HR=1.766;95%CI:1.017–3.065;P=0.043)and more advanced AKIstage(Stage 2:HR=3.063;95%CI:2.207–4.252;P<0.001;Stage 3:HR=7.333;95%CI:5.274–10.197;P<0.001)were independently associated with an increased risk of 1-year mortality.Conclusions:In very elderly AKI patients,both a higher stage and duration were independently associated withan increased risk of 1-year mortality.Hence,the duration of AKI adds additional information to predict long-termmortality.

Gene deficiency or pharmacological inhibition of PDCD4-mediated FGR signaling protects against acute kidney injury

Recent studies have shown that programmed cell death 4(PDCD4)modulates distinct signal transduction pathways in different pathological conditions.Despite acute and chronic immune responses elicited by ischemia contributing to the functional deterioration of the kidney,the contributions and mechanisms of PDCD4 in acute kidney injury(AKI)have remained unclear.Using two murine AKI models including renal ischemia/reperfusion injury(IRI)and cisplatin-induced AKI,we found that PDCD4 deficiency markedly ameliorated renal dysfunction and inflammatory responses in AKI mice.Consistently,upregulation of PDCD4 was also confirmed in the kidneys from patients with biopsy confirmed acute tubular necrosis from a retrospective cohort study.Moreover,we found that overexpression of Fgr,a member of the tyrosine kinase family,dramatically aggravated renal injury and counteracted the protective effects of PDCD4 deficiency in AKI mice.We discovered that FGR upregulated NOTCH1 expression through activating STAT3.Most importantly,we further found that systemic administration of ponatinib,a tyrosine kinase inhibitor,significantly ameliorated AKI in mice.In summary,we identified that PDCD4 served as an important regulator,at least in part,of FGR/NOTCH1-mediated tubular apoptosis and inflammation in AKI mice.Furthermore,our findings suggest that ponatinib-mediated pharmacologic targeting of this pathway had therapeutic potential for mitigating AKI.

Esculin alleviates acute kidney injury and inflammation induced by LPS in mice and its possible mechanism

Acute kidney injury(AKI)is a common clinical serious illness.Esculin(ES)is a coumarin compound of traditional Chinese medicine Cortex Fraxini.Our previous study has found that ES protects against inflammation and renal damage in diabetic rats.In the present study,we aimed to investigate the effects and the possible mechanism of ES against lipopolysaccharides(LPS)-induced AKI in mice.Renal morphology was observed by H&E staining.Renal function was evaluated by blood urea nitrogen(BUN)level and creatinine content in serum.Inflammatory factor levels were measured by ELISA assay.The inflammatory proteins were analyzed by RT-PCR and Western blotting analysis.The results showed that ES alleviated LPS-induced pathological injury and renal dysfunction,and decreased BUN level and creatinine content in serum.In addition,ES significantly reduced the release of pro-inflammatory factors,including IL-1β,IL-6 and TNF-α,chemokine MCP-1 and cell adhesion molecule ICAM-1.Furthermore,the expressions of inflammatory pathway proteins P2 X7,HMGB1,TLR4 and MyD88 both at the mRNA and protein levels were all down-regulated by ES in the kidney tissue of LPS-challenged mice.These results suggested ES protected against LPS-induced AKI through inhibiting P2 X7 expression and HMGB1/TLR4 inflammatory pathway.

The role of high mobility group box 1(HMGB1)in the pathogenesis of kidney diseases

High mobility group box 1 (HMGB1) is a nuclear protein that can bind to DNA and act as a co-factor for gene transcription. When released into extracellular fluid, it plays a proinflammatory role by acting as a damage-associated molecular pattern molecule (DAMP) (also known as an alarmin) to initiate innate immune responses by activating multiple cell surface receptors such as the receptor for advanced glycation end-products (RAGE) and toll-like receptors (TLRs), TLR2, TLR4 or TLR9. This proinflammatory role is now considered to be important in the pathogenesis of a wide range of kidney diseases whether they result from hemodynamic changes, renal tubular epithelial cell apoptosis, kidney tissue fibrosis or inflammation. This review summarizes our current understanding of the role of HMGB1 in kidney diseases and how the HMGB1-mediated signaling pathway may constitute a new strategy for the treatment of kidney diseases. (C) 2016 Chinese Pharmaceutical Association and Institute of Materia Medica, Chinese Academy of Medical Sciences. Production and hosting by Elsevier B.V.