The Inhibitory Impact of Schisandrin Against LPS-Induced Acute Kidney Injury in Vitro and in Vivo

Abstract Schisandrin (Sch) is a main bioactive component of Schisandra sphenanthera Rehd.et Wils. It has been reported that Sch could regulate inflammatory disease. This study evaluated the anti-inflammatory and anti-oxidant effects effect of Sch on lipopolysaccharide (LPS)-induced macrophages activation and acute kidney injury mice. Male Kunming mice were intraperitoneally injected with LPS (15 mg/kg) after administration of Sch (12.5, 25, 50 mg/kg) seven days for developing acute kidney injury vivo model. RAW264.7 macrophages were pretreatment Sch (10, 20, 40 µM) and administrated LPS (1 µg/ml) to create an in vitro injury model. ELISA results found that Sch administration reduced the production of inflammatory factors induced by LPS in kidney tissues and RAW264.7 macrophages. It has been observed that Sch alleviated oxidative stress by reducing the levels of reactive oxygen species, myeloperoxidase and malondialdehyde, and increasing the activity of superoxide dismutase and glutathione peroxidase. Hematoxylin-eosin staining data suggested that Sch administration significantly reduced inflammatory cell infiltration and the kidney tissue damage induced by LPS. The blood urea nitrogen and creatinine levels were also reduced by Sch treatment. In addition, Western blot and immunohistochemical analysis showed that Sch up-regulated the expression of Nrf2 and HO-1, and decreased the expression of p-p38, p-JNK, p-ERK1/2, p-IκBα, p-NF-κBp65 and TLR4. The current research showed that Sch reduced LPS-induced acute kidney injury by inhibiting inflammation and oxidative stress, and provided insights into potential ways to treat AKI.

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The Protective Effect of Sika Deer Antler Protein on Gentamicin-Induced Nephrotoxicity in Vitro and in Vivo

Cellular Physiology and Biochemistry ◽

10.1159/000494471 ◽

2018 ◽

Vol 50 (3) ◽

pp. 841-850 ◽

Cited By ~ 4

Author(s):

Hang Sun ◽

Huihai Yang ◽

Haonan Ruan ◽

Wei Li ◽

Xinhong He ◽

...

Keyword(s):

Oxidative Stress ◽

Sika Deer ◽

Kidney Injury ◽

Hek293 Cells ◽

Inflammatory Factors ◽

Oxidative Stress Marker ◽

Renal Protection ◽

Deer Antler

Background/Aims: Sika deer (Cervus nippon Temminck) antler is traditional animal medicine of renal protection in East Asia. This study measured the effect of sika deer antler protein (SDAPR) on gentamicin (GM)-induced cytotoxicity in HEK293 cells, and investigated the effect of SDAPR against GM-induced nephrotoxicity in mice. Methods: HEK293 cells viability and oxidative stress were measured in HEK293 cells while flow cytometry was used for apoptosis analysis. The acute kidney injury biomarkers, kidney injury molecule-1 (KIM-1), neutrophil gelatinase-associated lipocalin (NGAL) and cystatin c (Cys-C), were repeatedly measured by ELISA assay. ICR male mice were randomly assigned six groups: Control, GM with vehicle, single SDAPR, GM with SDAPR at three concentrations 50, 100, 200 mg/kg/d, p.o., 10 d. GM was injected for 8 consecutive days (100 mg/kg/d, i.p.). Renal function, oxidative stress and levels of inflammatory factors were measured in vivo. Renal tissues were stained with H&E to observe pathological changes. Results: Pretreatment with SDAPR (0.5-4.0 mg/mL) significantly improved cell viability. Treatment with SDAPR could reduce KIM-1, NGAL and Cys-C activity. SDAPR could improve antioxidant defense and attenuated apoptosis on HEK293 cells. SDAPR also ameliorated GM-induced histopathologic changes, and decreased blood urea nitrogen (BUN) and serum creatinine (Cr). Additionally, SDAPR significantly regulated oxidative stress marker and interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) inflammatory cytokines. Conclusion: These results show that SDAPR could be an effective dietary supplement to relieve GM-induced nephrotoxicity by improved antioxidase activity, suppressed inflammation, and inhibited apoptosis in vitro and vivo.

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Premobilization of CD133+ progenitors is associated with attenuated inflammation-induced pulmonary dysfunction following extracorporeal circulation in mice

Interactive Cardiovascular and Thoracic Surgery ◽

10.1093/icvts/ivaa074 ◽

2020 ◽

Vol 31 (2) ◽

pp. 210-220

Author(s):

Dan Luo ◽

Xinhao Liu ◽

Jie Zhang ◽

Lei Du ◽

Lin Bai ◽

...

Keyword(s):

Acute Kidney Injury ◽

Lung Injury ◽

Bronchoalveolar Lavage ◽

Lung Tissue ◽

Extracorporeal Circulation ◽

Kidney Injury ◽

Inflammatory Factors ◽

Pulmonary Dysfunction

Abstract OBJECTIVES Progenitor cells mobilized by granulocyte colony-stimulating factor (G-CSF) have been shown to lessen acute kidney injury induced by extracorporeal circulation (ECC). Both acute kidney injury and lung injury are characterized by endothelial dysfunction. Our goal was to examine whether and how G-CSF-mobilized progenitors with endothelial capacity may help mitigate ECC-induced pulmonary dysfunction. METHODS G-CSF (10 μg/kg/day) was administered subcutaneously to C57BL/6 mice before or at the initiation of the ECC process, after which lung injury was assessed by measuring neutrophils in the fluid from bronchoalveolar lavage and determining the pathological score in lung tissue. CD133+ progenitors were isolated and injected into C57BL/6 mice before ECC in vivo. We incubated the CD133+ cells with pulmonary monocytes or neutrophils isolated from naïve mice in vitro. RESULTS Pretreatment with G-CSF for 2 days significantly decreased the number of neutrophils in the bronchoalveolar lavage fluid, and the pathological score (P < 0.01; n = 5) improved the PaO2/FiO2 ratio [193.4 ± 12.7 (ECC without G-CSF) vs 305.6 ± 22.6 mmHg (ECC with G-CSF); P = 0.03, n = 5] and suppressed neutrophil elastase and tumour necrosis factor-α levels in the circulation; we also observed increases in both circulating and pulmonary populations of CD133+ progenitors. Similar effects were observed in animals pretreated with CD133+ progenitors instead of G-CSF before ECC. The majority of CD133+/CD45− and CD133+/CD45+ progenitors were mobilized in the lung and in the circulation, respectively. Incubating CD133+ progenitors with neutrophils or pulmonary monocytes blocked lipopolysaccharide-induced release of inflammatory factors. CONCLUSIONS Our results suggest that pretreatment of G-CSF attenuates ECC-induced pulmonary dysfunction through inhibiting the inflammatory response in lung tissue and in the circulation with associated premobilization of CD133+ progenitors.

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The Mimetic Peptide Ac2-26 of Annexin A1 Attenuates Inflammation and Apoptosis in Sepsis-Induced Acute Kidney Injury

10.21203/rs.3.rs-135005/v1 ◽

2020 ◽

Author(s):

Yanlei Zheng ◽

Ronghua Hu ◽

Li Zhang

Keyword(s):

Acute Kidney Injury ◽

Kidney Function ◽

Kidney Tissue ◽

Kidney Injury ◽

Annexin A1 ◽

Mimetic Peptide ◽

Associated Proteins ◽

Inflammatory Molecules

Abstract BackgroundInflammation and apoptosis contribute to the development of sepsis-induced acute kidney injury. Annexin A1 (ANXA1) is the calcium-dependent phospholipid-binding protein known to play an important role in a variety of cellular functions, including inflammation, apoptosis, migration and proliferation. However, the effect of ANXA1 on sepsis-induced acute injury has not been reported. Herein, we investigated the role and underlying mechanism of the mimetic peptide Ac2-26 of annexin A1 in sepsis-induce acute kidney injury in vivo and in vitro.MethodsIn vivo, a mouse model was established by cecal ligation and puncture (CLP), and the Ac2-26 peptide of ANXA1 (1 mg/kg) was intraperitoneally administered 2 hours before CLP. In vitro, A model of HK-2 cells was established by treatment with 10 μg/ml lipopolysaccharide (LPS), and the Ac2-26 peptide of ANXA1 (0.5 μmol/L) was administered 2 hours before LPS. The kidney function of mice detected by Elisa. The kidney tissue was examined by HE and TEM. The inflammatory cytokines and apoptotic molecules were measured by PCR, Elisa, Western blotting and Immunohistochemistry. The apoptosis was detected by TUNEL and flow cytometry.ResultsThe studies demonstrated that ANXA1 markedly improved kidney function and kidney tissue injury and enhanced 7-day survival in CLP-induced septic mice, which was accompanied by a significant decrease the inflammatory molecules. ANXA1 obviously downregulated the apoptosis-associated proteins and inhibited apoptosis in kidney tissue in vivo. In vitro studies showed that ANXA1 increased the viability of HK-2 cells, reduced the levels of the inflammatory molecules, downregulated the apoptosis-associated proteins Bax, upregulated the antiapoptotic protein Bcl-2 and inhibited the apoptosis of HK-2 cells.ConclusionsThe mimetic peptide Ac2-26 of annexin A1 protects against sepsis-induced inflammation, apoptosis, and kidney dysfunction via regulating the LXA4/PI3K/IKK-β/NF-κB signaling pathway.

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Melatonin Alleviates Contrast-Induced Acute Kidney Injury by Activation of Sirt3

Oxidative Medicine and Cellular Longevity ◽

10.1155/2021/6668887 ◽

2021 ◽

Vol 2021 ◽

pp. 1-21

Author(s):

Chunmei Zhang ◽

Mengying Suo ◽

Lingxin Liu ◽

Yan Qi ◽

Chen Zhang ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Transforming Growth Factor ◽

Kidney Injury ◽

Transforming Growth Factor Β ◽

Activity Levels ◽

Protective Effects ◽

Melatonin Treatment

Oxidative stress and apoptosis play a vital role in the pathogenesis of contrast-induced acute kidney injury (CI-AKI). The purpose of our study was to investigate the protective effects and mechanisms of melatonin against CI-AKI in a CI-AKI mouse model and NRK-52E cells. We established the CI-AKI model in mice, and the animals were pretreated with melatonin (20 mg/kg). Our results demonstrated that melatonin treatment exerted a renoprotective effect by decreasing the level of serum creatinine (SCr) and blood urea nitrogen (BUN), lessening the histological changes of renal tubular injuries, and reducing the expression of neutrophil gelatinase-associated lipid (NGAL), a marker of kidney injury. We also found that pretreatment with melatonin remarkably increased the expression of Sirt3 and decreased the ac-SOD2 K68 level. Consequently, melatonin treatment significantly decreased the oxidative stress by reducing the Nox4, ROS, and malondialdehyde (MDA) content and by increasing the superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px) activity levels. The antiapoptotic effect of melatonin on CI-AKI was revealed by decreasing the ratio of Bax/Bcl2 and the cleaved caspase3 level and by reducing the number of apoptosis-positive tubular cells. In addition, melatonin treatment remarkably reduced the inflammatory cytokines of interleukin-1β (IL-1β), tumor necrosis factor α (TNFα), and transforming growth factor β (TGFβ) in vivo and in vitro. Sirt3 deletion and specific Sirt3 siRNA abolished the above renoprotective effects of melatonin in mice with iohexol-induced acute kidney injury and in NRK-52E cells. Thus, our results demonstrated that melatonin exhibited the renoprotective effects of antioxidative stress, antiapoptosis, and anti-inflammation by the activation of Sirt3 in the CI-AKI model in vivo and in vitro. Melatonin may be a potential drug to ameliorate CI-AKI in clinical practice.

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Inhibition of gap junction composed of Cx43 prevents against acute kidney injury following liver transplantation

Cell Death and Disease ◽

10.1038/s41419-019-1998-y ◽

2019 ◽

Vol 10 (10) ◽

Cited By ~ 3

Author(s):

Dongdong Yuan ◽

Xiaoyun Li ◽

Chenfang Luo ◽

Xianlong Li ◽

Nan Cheng ◽

...

Keyword(s):

Oxidative Stress ◽

Liver Transplantation ◽

Acute Kidney Injury ◽

Kidney Injury ◽

Protective Effects ◽

Sprague Dawley ◽

Organ Protection ◽

Cx43 Expression

Abstract Postoperative acute kidney injury (AKI) is a severe complication after liver transplantation (LT). Its deterioration and magnification lead to the increase in mortality. Connexin43 (Cx43) mediates direct transmission of intracellular signals between neighboring cells, always considered to be the potent biological basis of organ damage deterioration and magnification. Thus, we explored the effects of Cx43 on AKI following LT and its related possible mechanism. In this study, alternations of Cx43 expression were observed in 82 patients, receiving the first-time orthotopic LT. We built autologous orthotopic liver transplantation (AOLT) models with Sprague–Dawley (SD) rats in vivo, and hypoxia-reoxygenation (H/R) or lipopolysaccharide (LPS) pretreatment models with kidney tubular epithelial cells (NRK-52E) in vitro, both of which were the most important independent risk factors of AKI following LT. Then, different methods were used to alter the function of Cx43 channels to determine its protective effects on AKI. The results indicated that patients with AKI suffering from longer time of tracheal intubation or intensive care unit stay, importantly, had significantly lower survival rate at postoperative 30 days and 3 years. In rat AOLT models, as Cx43 was inhibited with heptanol, postoperative AKI was attenuated significantly. In vitro experiments, downregulation of Cx43 with selective inhibitors, or siRNA protected against post-hypoxic NRK-52E cell injuries caused by H/R and/or LPS, while upregulation of Cx43 exacerbated the above-mentioned cell injuries. Of note, alternation of Cx43 function regulated the content of reactive oxygen species (ROS), which not only mediated oxidative stress and inflammation reactions effectively, but also regulated necroptosis. Therefore, we concluded that Cx43 inhibition protected against AKI following LT through attenuating ROS transmission between the neighboring cells. ROS alternation depressed oxidative stress and inflammation reaction, which ultimately reduced necroptosis. This might offer new insights for targeted intervention for organ protection in LT, or even in other major surgeries.

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Curcumin-Loaded Nanoparticles Protect Against Rhabdomyolysis-Induced Acute Kidney Injury

Cellular Physiology and Biochemistry ◽

10.1159/000484233 ◽

2017 ◽

Vol 43 (5) ◽

pp. 2143-2154 ◽

Cited By ~ 16

Author(s):

Xiaoling Chen ◽

Jian Sun ◽

Hailun Li ◽

Hongwu Wang ◽

Yongtao Lin ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Treatment Efficacy ◽

Kidney Injury ◽

In Vivo Studies ◽

Renal Tubules ◽

Drug Release Profile ◽

Renal Tubular

Background/Aims: Rhabdomyolysis (RM) is a potentially life-threatening condition that results from the breakdown of muscle and consequent release of toxic compounds into circulation. The most common and severe complication of RM is acute kidney injury (AKI). This study aimed to evaluate the efficacy and mechanisms of action of curcumin-loaded nanoparticles (Cur-NP) for treatment of RM-induced AKI. Methods: Curcumin-NP was synthesized using the nanocarrier distearoylphosphatidylethanolamine-polyethylene glycol (DSPE-PEG) to achieve a prolonged and constant drug release profile compared with the curcumin-free group. The anti-AKI effects of Curcumin-NP were examined both in vitro (myoglobin-treated renal tubular epithelial HK-2 cells) and in vivo (glycerol-induced AKI model). Results: Our results indicated that Curcumin-NP reversed oxidative stress, growth inhibition and cell apoptosis accompanied with down-regulation of apoptotic markers Caspase-3 and GRP-78 in vitro. In vivo studies revealed enhanced AKI treatment efficacy with Curcumin-NP as characterized by reduced serum creatine phosphokinase (CPK), creatinine (Cr) and urea and less severe histological damage in renal tubules. In addition, kidney tissues from Curcumin-NP-treated AKI rats exhibited reduced oxidative stress, apoptosis, and cleaved Capase-3 and GRP-78 expression. Conclusion: Our results suggest that nanoparticle-loaded curcumin enhances treatment efficacy for RM-induced AKI both in vitro and in vivo.

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Involvement of S100A8/A9-TLR4-NLRP3 Inflammasome Pathway in Contrast-Induced Acute Kidney Injury

Cellular Physiology and Biochemistry ◽

10.1159/000480340 ◽

2017 ◽

Vol 43 (1) ◽

pp. 209-222 ◽

Cited By ~ 19

Author(s):

Xuexian Tan ◽

Xiaohe Zheng ◽

Zena Huang ◽

Jiaqiong Lin ◽

Chuli Xie ◽

...

Keyword(s):

Acute Kidney Injury ◽

Nlrp3 Inflammasome ◽

Tissue Injury ◽

Kidney Tissue ◽

Kidney Injury ◽

Underlying Mechanism ◽

Male Rats ◽

Ros Generation

Background: Contrast-induced acute kidney injury (CIAKI) is a common cause of hospital-acquired acute kidney injury (AKI). S100A8/A9-TLR4-NLRP3 inflammasome pathway triggers inflammation, apoptosis and tissue injury in several AKI models. Nevertheless, the underlying mechanism of S100A8/A9-TLR4-NLRP3 inflammasome pathway in CIKAI is not clear. We aimed to investigate the possible role of S100A8/A9-TLR4-NLRP3 inflammasome in the pathophysiology of CIAKI. Methods: We treated male rats and NRK-52E cells by iopromide to establish in vivo and in vitro models of CIAKI. We collected serum and urine samples to detect renal function. We obtained kidney tissue for histological analysis and detection of protein concentration. We used inhibitor of TLR4 and NLRP3-siRNA to further testify their role in CIAKI in NRK-52E cells. Results: Iopromide caused elevation of SCr, BUN and NGAL level, decrease of endogenous creatinine clearance, morphological injury and tubular apoptosis, enhanced IL-1β and IL-18 expression, and increased expression of S100A8/A9, TLR4 and NLRP3 inflammsome. In NRK-52E cells, iopromide caused enhanced apoptotic rates and ROS generation, which could be ameliorated by inhibitor of TLR4 and NLRP3-siRNA. Moreover, inhibition of TLR4 dampened NLRP3 expression. Conclusion: S100A8/A9-TLR4-NLRP3 inflammasome pathway represented a key mechanism of CI-AKI, which provided a potential therapeutic target.

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LncRNA TUG1 regulates the development of ischemia-reperfusion mediated acute kidney injury through miR-494-3p/E-cadherin axis

Journal of Inflammation ◽

10.1186/s12950-021-00278-4 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Li Chen ◽

Jun-Ying Xu ◽

Hong-Bao Tan

Keyword(s):

Acute Kidney Injury ◽

Cell Apoptosis ◽

Ischemia Reperfusion ◽

Kidney Tissue ◽

Kidney Injury ◽

Luciferase Assay ◽

Lncrna Tug1 ◽

E Cadherin

AbstractBackgroundAcute kidney injury (AKI) results from renal dysfunction caused by various causes, resulting in high mortality. The underlying mechanisms of ischemia-reperfusion (I/R) induced AKI is very complicated and needed for further research. Here, we sought to found out the functions of lncRNA TUG1 in I/R-induced AKI.MethodsIn vivo model was constructed by I/R-induced mice and in vitro model was constructed by hypoxia/reoxygenation (H/R)-induced HK-2 cell. Kidney tissue damage was evaluated through H&E staining in mice. Cell flow cytometry was used to detect the degree of apoptosis. TUG1, miR-494-3p and E-cadherin were determined both by RT-PCR and western blot. Dual luciferase assay was employed to validate the relationships between TUG1, miR-494-3p and E-cadherin. Inflammatory factors including IL-1β, TNFɑ and IL-6 were evaluated by ELISA.ResultslncRNA TUG1 was decreased while miR-494-3p was elevated in vivo and in vitro. Overexpression of TUG1 or transfection with miR-494-3p inhibitor significantly alleviated cell apoptosis. MiR-494-3p directly targeted E-cadherin and TUG1 suppressed cell apoptosis via serving as a miR-494-3p sponge to disinhibit E-cadherin.ConclusionlncRNA TUG1 alleviated I/R-induced AKI through targeting miR-494-3p/E-cadherin.

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miR-141 mediates recovery from acute kidney injury

Scientific Reports ◽

10.1038/s41598-021-94984-x ◽

2021 ◽

Vol 11 (1) ◽

Author(s):

Lucy J. Newbury ◽

Kate Simpson ◽

Usman Khalid ◽

Imogen John ◽

Lluís Bailach de Rivera ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Cell Viability ◽

Messenger Rna ◽

Tyrosine Phosphatase ◽

Kidney Injury ◽

Clinical Problem ◽

Proximal Tubular

AbstractAcute kidney injury (AKI) is a global clinical problem characterised by a sudden decline in renal function and mortality as high as 60%. Current AKI biomarkers have limited ability to classify disease progression and identify underlying pathological mechanisms. Here we hypothesised that alterations in urinary microRNA profiles could predict AKI recovery/nonrecovery after 90 days, and that injury-specific changes would signify microRNA mediators of AKI pathology. Comparison of urinary microRNA profiles from AKI patients with controls detected significant injury-specific increases in miR-21, miR-126 and miR-141 (p < 0.05) and decreases in miR-192 (p < 0.001) and miR-204 (p < 0.05). Expression of miR-141 increased in renal proximal tubular epithelial cells (PTECs) under oxidative stress in vitro and unilateral ischaemic reperfusion injury in vivo. Forced miR-141 expression in the presence of H2O2 increased PTEC death and decreased cell viability. Of nine messenger RNA targets with two or more miR-141 3’-untranslated region binding sites, we confirmed protein tyrosine phosphatase receptor type G (PTPRG) as a direct miR-141 target in PTECs. PTPRG-specific siRNA knockdown under oxidative stress increased PTEC death and decreased cell viability. In conclusion, we detected significant alterations in five urinary microRNAs following AKI, and identified proximal tubular cell PTPRG as a putative novel therapeutic target.

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Kidney Organoids as a Novel Platform to Evaluate Lipopolysaccharide-Induced Oxidative Stress and Apoptosis in Acute Kidney Injury

Frontiers in Medicine ◽

10.3389/fmed.2021.766073 ◽

2021 ◽

Vol 8 ◽

Author(s):

Weitao Zhang ◽

Ruochen Qi ◽

Tingting Li ◽

Xuepeng Zhang ◽

Yi Shi ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Immune Cell ◽

Kidney Injury ◽

Human Kidney ◽

Kidney Cells ◽

Pathological Changes ◽

Kidney Organoids

Sepsis-associated acute kidney injury (SA-AKI) is a life-threatening syndrome. Lipopolysaccharide (LPS) is a widely used inducer for modeling SA-AKI both in vivo and in vitro. However, due to the innate complexity of the kidney architecture, the mechanisms underlying the pathogenesis of SA-AKI, as well as those involved in LPS-induced kidney injury remain to be clarified. Kidney organoids derived from human pluripotent stem cells (hPSCs) act as a model of multiple types of kidney cells in vitro and eliminate potential confounders in vivo. In the current study, we established LPS-induced kidney injury models both in vivo and in human kidney organoids. Kidney function, pathological changes, and markers of oxidative stress were evaluated with/without the presence of methylprednisolone (MP) treatment both in vivo and in vitro. The extent of LPS-induced oxidative stress and apoptosis in kidney organoids was further investigated in vitro. LPS-induced acute kidney injury in mice, together with pathological changes and increased oxidative stress, as well as enhanced apoptosis in kidney cells were evaluated. These phenomena were ameliorated by MP treatment. Experiments in kidney organoids showed that the LPS-induced apoptotic effects occurred mainly in podocytes and proximal tubular cells. Our experiments demonstrated the efficacy of using kidney organoids as a solid platform to study LPS-induced kidney injury. LPS induced oxidative stress as well as apoptosis in kidney cells independently of changes in perfusion or immune cell infiltration. MP treatment partially alleviated LPS-induced injury by reducing kidney cell oxidative stress and apoptosis.

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