Neuregulin-1β Protects the Rat Diaphragm during Sepsis against Oxidative Stress and Inflammation by Activating the PI3K/Akt Pathway

Sepsis-induced diaphragm dysfunction (SIDD) which is mainly characterized by decrease in diaphragmatic contractility has been identified to cause great harms to patients. Therefore, there is an important and pressing need to find effective treatments for improving SIDD. In addition, acetylcholinesterase (AChE) activity is a vital property of the diaphragm, so we evaluated both diaphragmatic contractility and AChE activity. Though neuregulin-1β (NRG-1β) is known to exert organ-protective effects in some inflammatory diseases, little is known about the potential of NRG-1β therapy in the diaphragm during sepsis. Our study was aimed at exploring the effects of NRG-1β application on diaphragmatic contractility and AChE activity during sepsis. Proinflammatory cytokines, muscle injury biomarkers in serum, contractile force, AChE activity, proinflammatory cytokines, oxidative parameters, histological condition, terminal deoxynucleotidyl transferase-mediated dUTP nick end labeling (TUNEL) staining, and expression of phosphoinositide 3-kinase (PI3K)/protein kinase B (PKB/Akt) signaling proteins in the diaphragm were measured and compared between nonseptic and septic groups with or without NRG-1β treatment. In vitro, the effects of NRG-1β on reactive oxygen species (ROS) production in the lipopolysaccharide- (LPS-) stimulated L6 rat muscle skeletal cells with or without the Akt inhibitor MK-2206 were detected. NRG-1β inhibited proinflammatory cytokine release and muscle injury biomarkers soaring in serum and improved the sepsis-induced diaphragm dysfunction and AChE activity decrease significantly during sepsis. Meanwhile, the inflammatory response, oxidative stress, pathological impairment, and cell apoptosis in the diaphragm were mitigated by NRG-1β. And NRG-1β activated the PI3K/Akt signaling in the diaphragm of septic rats. Elevated ROS production in the LPS-stimulated L6 rat skeletal muscle cells was reduced after treatment with NRG-1β, while MK-2206 blocked these effects of NRG-1β. In conclusion, our findings underlined that NRG-1β could reduce circulating levels of proinflammatory cytokines in rats with sepsis, adjust diaphragmatic proinflammatory cytokine level, mitigate diaphragmatic oxidative injury, and lessen diaphragm cell apoptosis, thereby improving diaphragmatic function, and play a role in diaphragmatic protection by activating PI3K/Akt signaling.

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l-Arginine Alleviates LPS-Induced Oxidative Stress and Apoptosis via Activating SIRT1-AKT-Nrf2 and SIRT1-FOXO3a Signaling Pathways in C2C12 Myotube Cells

Antioxidants ◽

10.3390/antiox10121957 ◽

2021 ◽

Vol 10 (12) ◽

pp. 1957

Author(s):

Ye Zhao ◽

Qin Jiang ◽

Xuefei Zhang ◽

Xiaoxiao Zhu ◽

Xia Dong ◽

...

Keyword(s):

Oxidative Stress ◽

Signaling Pathways ◽

Cell Apoptosis ◽

Muscle Injury ◽

Protective Mechanism ◽

Nrf2 Signaling Pathway ◽

Wide Range ◽

Range Of Functions ◽

Sirt1 Inhibitor ◽

C2c12 Myotube

l-arginine (l-Arg) has been reported to possess a wide range of functions, including anti-inflammatory, anti-oxidative, and anti-apoptosis. However, the role of l-Arg in LPS-induced muscle injury and its potential protective mechanism has not been well elucidated. This study aimed to investigate the effects of l-Arg on the LPS-induced oxidative stress and apoptosis in differentiated C2C12 myotube cells. Our results demonstrated that myotube cells treated with 0.2 mg/mL LPS significantly decreased cell viability. l-Arg treatment significantly suppressed LPS induced ROS accumulation and cell apoptosis. Furthermore, l-Arg improved antioxidant-related enzymes’ activities; increased antioxidant ability via Akt-Nrf2 signaling pathway; maintained the mitochondrial membrane potential (MMP); and enhanced FOXO3a expression, leading to a decrease in the mitochondrial-associated apoptotic proteins. In addition, l-Arg exposure dramatically increased the mRNA and protein expressions of SIRT1. The cytoprotective effect of l-Arg was restricted by the SIRT1 inhibitor EX527, which led to an increase in ROS level, apoptosis rate, and decreased cell MMP. The results also demonstrated that EX527 treatment significantly eliminated the effect of l-Arg on LPS-induced oxidative damage and mitochondria-mediated cell apoptosis. Our findings revealed that l-Arg could be used as a potential nutraceutical in reducing muscle injury via regulating SIRT1-Akt-Nrf2 and SIRT1-FOXO3a-mitochondria apoptosis signaling pathways.

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Astaxanthin Protects Retinal Photoreceptor Cells against High Glucose-Induced Oxidative Stress by Induction of Antioxidant Enzymes via the PI3K/Akt/Nrf2 Pathway

Antioxidants ◽

10.3390/antiox9080729 ◽

2020 ◽

Vol 9 (8) ◽

pp. 729 ◽

Cited By ~ 4

Author(s):

Tso-Ting Lai ◽

Chung-May Yang ◽

Chang-Hao Yang

Keyword(s):

Oxidative Stress ◽

High Glucose ◽

Cell Apoptosis ◽

Photoreceptor Cells ◽

Nutritional Supplement ◽

Free Radical Scavenger ◽

Radical Scavenger ◽

Ros Production ◽

Nrf2 Pathway ◽

Patients With Diabetes

Diabetic retinopathy (DR) is a major microvascular complication that can lead to severe visual impairment in patients with diabetes. The elevated oxidative stress and increased reactive oxygen species (ROS) production induced by hyperglycemia have been reported to play an important role in the complex pathogenesis of DR. Astaxanthin (AST), a natural carotenoid derivative, has been recently recognized as a strong free radical scavenger and might, therefore, be beneficial in different diseases, including DR. In this study, we evaluated the potential role of AST as an antioxidative and antiapoptotic agent in protecting retinal cells and also investigated the involvement of the PI3K/Akt/Nrf2 pathway in AST-mediated effects. We treated high glucose-cultured mouse photoreceptor cells (661W) with different concentrations of AST and analyzed ROS production and cell apoptosis in the different regimens. Moreover, we also analyzed the expression of PI3K, Akt, Nrf2, and Phase II enzymes after AST treatment. Our results showed that AST dose-dependently reduced ROS production and attenuated 661W cell apoptosis in a high glucose environment. Importantly, its protective effect was abolished by treatment with PI3K or Nrf2 inhibitors, indicating the involvement of the PI3K/Akt/Nrf2 pathway. These results suggest AST as a nutritional supplement that could benefit patients with DR.

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Evidence of Contribution of iPLA2β-Mediated Events During Islet β-Cell Apoptosis Due to Proinflammatory Cytokines Suggests a Role for iPLA2β in T1D Development

Endocrinology ◽

10.1210/en.2013-2134 ◽

2014 ◽

Vol 155 (9) ◽

pp. 3352-3364 ◽

Cited By ~ 14

Author(s):

Xiaoyong Lei ◽

Robert N. Bone ◽

Tomader Ali ◽

Sheng Zhang ◽

Alan Bohrer ◽

...

Keyword(s):

Er Stress ◽

Proinflammatory Cytokines ◽

Cell Apoptosis ◽

Proinflammatory Cytokine ◽

Immune Cell ◽

Regulatory Element ◽

Cell Mass ◽

Β Cells ◽

Β Cell ◽

Underlying Mechanisms

Abstract Type 1 diabetes (T1D) results from autoimmune destruction of islet β-cells, but the underlying mechanisms that contribute to this process are incompletely understood, especially the role of lipid signals generated by β-cells. Proinflammatory cytokines induce ER stress in β-cells and we previously found that the Ca2+-independent phospholipase A2β (iPLA2β) participates in ER stress-induced β-cell apoptosis. In view of reports of elevated iPLA2β in T1D, we examined if iPLA2β participates in cytokine-mediated islet β-cell apoptosis. We find that the proinflammatory cytokine combination IL-1β+IFNγ, induces: a) ER stress, mSREBP-1, and iPLA2β, b) lysophosphatidylcholine (LPC) generation, c) neutral sphingomyelinase-2 (NSMase2), d) ceramide accumulation, e) mitochondrial membrane decompensation, f) caspase-3 activation, and g) β-cell apoptosis. The presence of a sterol regulatory element in the iPLA2β gene raises the possibility that activation of SREBP-1 after proinflammatory cytokine exposure contributes to iPLA2β induction. The IL-1β+IFNγ-induced outcomes (b–g) are all inhibited by iPLA2β inactivation, suggesting that iPLA2β-derived lipid signals contribute to consequential islet β-cell death. Consistent with this possibility, ER stress and β-cell apoptosis induced by proinflammatory cytokines are exacerbated in islets from RIP-iPLA2β-Tg mice and blunted in islets from iPLA2β-KO mice. These observations suggest that iPLA2β-mediated events participate in amplifying β-cell apoptosis due to proinflammatory cytokines and also that iPLA2β activation may have a reciprocal impact on ER stress development. They raise the possibility that iPLA2β inhibition, leading to ameliorations in ER stress, apoptosis, and immune responses resulting from LPC-stimulated immune cell chemotaxis, may be beneficial in preserving β-cell mass and delaying/preventing T1D evolution.

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L-Arginine Alleviates LPS-induced Oxidative Stress and Apoptosis via Activating SIRT1-AKT-Nrf2 and SIRT1-FOXO3a Signaling Pathways in C2C12 Myotube Cells

10.21203/rs.3.rs-1045345/v1 ◽

2021 ◽

Author(s):

Ye Zhao ◽

Qin Jiang ◽

Xuefei Zhang ◽

Xiaoxiao Zhu ◽

Xia Dong ◽

...

Keyword(s):

Oxidative Stress ◽

Signaling Pathways ◽

Cell Apoptosis ◽

Muscle Injury ◽

In Vitro Models ◽

Protective Mechanism ◽

Nrf2 Signaling Pathway ◽

Wide Range ◽

C2c12 Myotube

Abstract BackgroundAs a highly plasticized tissue, muscle could exert a spontaneous immune behavior in response to external pathogen stimulation. L-arginine (L-Arg) has been reported to possess a wide range of functions, including anti-inflammatory, anti-oxidative, and anti-apoptosis. However, the role of L-Arg in LPS-induced muscle injury and its potential protective mechanism has not been well elucidated. This study aimed to investigate the effects of L-Arg on the LPS-induced oxidative stress and apoptosis in vitro models of well-differentiated C2C12 myotube cells. ResultsIn the present study, we first demonstrated that myotube cells treated with 0.2 mg/mL lipopolysaccharide (LPS) significantly decreased cell viability. Then, different concentrations of L-Arg (0, 0.5, 2.5, 5 mM)-pretreated myotube cells were exposed to LPS. The results showed that L-Arg treatment significantly suppressed reactive oxygen species (ROS) accumulation and cell apoptosis. Furthermore, L-Arg improved antioxidant-related enzymes’ activities; increased antioxidant ability via Akt-Nrf2 signaling pathway; maintained the mitochondrial membrane potential (MMP) and enhanced forkhead box protein 3a (FOXO3a) expression, lead to a decrease in the mitochondrial-associated apoptotic proteins. In addition, L-Arg exposure dramatically increased the mRNA and protein expressions of Sirtuin1 (SIRT1). The cytoprotective effect of L-Arg was restricted by the SIRT1 inhibitor EX527, which led to an increase in ROS level, apoptosis rate, and decreased cell MMP. The results also demonstrated that EX527 treatment significantly eliminated the effect of L-Arg on LPS-induced oxidative damage and mitochondria-mediated cell apoptosis. ConclusionsOur findings revealed that L-Arg could be used as a potential nutraceutical in reducing muscle injury via regulating SIRT1-Akt-Nrf2 and SIRT1-FOXO3a-mitochondria apoptosis signaling pathways.

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PARK7 Protects Against Chronic Kidney Injury and Renal Fibrosis by Inducing SOD2 to Reduce Oxidative Stress

Frontiers in Immunology ◽

10.3389/fimmu.2021.690697 ◽

2021 ◽

Vol 12 ◽

Author(s):

Lijun Yin ◽

Honglin Li ◽

Zhiwen Liu ◽

Wenwen Wu ◽

Juan Cai ◽

...

Keyword(s):

Oxidative Stress ◽

Cell Apoptosis ◽

Renal Fibrosis ◽

Kidney Diseases ◽

Kidney Injury ◽

Ros Production ◽

Tubular Cells ◽

Renal Tubular Cells ◽

Chronic Kidney Injury ◽

Renal Tubular

Renal fibrosis is the final common pathway to chronic kidney diseases regardless of etiology. Parkinson disease protein 7 (PARK7) is a multifunctional protein involved in various cellular processes, but its pathophysiological role in kidneys remain largely unknown. Here, we have determined the role of PARK7 in renal fibrosis and have further elucidated the underlying mechanisms by using the in vivo mouse model of unilateral ureteric obstruction (UUO) and the in vitro model of transforming growth factor-b (TGFB1) treatment of cultured kidney proximal tubular cells. PARK7 decreased markedly in atrophic kidney tubules in UUO mice, and Park7 deficiency aggravated UUO-induced renal fibrosis, tubular cell apoptosis, ROS production and inflammation. In vitro, TGFB1 treatment induced fibrotic changes in renal tubular cells, which was accompanied by alterations of PARK7. Park7 knockdown exacerbated TGFB1-induced fibrotic changes, cell apoptosis and ROS production, whereas Park7 overexpression or treatment with ND-13 (a PARK7-derived peptide) attenuated these TGFB1-induced changes. Mechanistically, PARK7 translocated into the nucleus of renal tubular cells following TGFB1 treatment or UUO, where it induced the expression of SOD2, an antioxidant enzyme. Taken together, these results indicate that PARK7 protects against chronic kidney injury and renal fibrosis by inducing SOD2 to reduce oxidative stress in tubular cells.

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MicroRNA-124 Prevents H2O2-Induced Apoptosis and Oxidative Stress in Human Lens Epithelial Cells via Inhibition of the NF-κB Signaling Pathway

Pharmacology ◽

10.1159/000491433 ◽

2018 ◽

Vol 102 (3-4) ◽

pp. 213-222 ◽

Cited By ~ 5

Author(s):

Xiu-li Gu

Keyword(s):

Oxidative Stress ◽

Epithelial Cells ◽

Signaling Pathway ◽

Cell Apoptosis ◽

Human Lens ◽

Lens Epithelial Cells ◽

Ros Production ◽

Human Lens Epithelial Cells ◽

Induced Apoptosis ◽

And Oxidative Stress

Aim: To investigate the regulation of microRNA-124 (miRNA-124) on NF-κB pathway from H2O2-induced apoptosis and oxidative stress in human lens epithelial cells (hLEC). Methods: The MTT (3-[4, 5-dimethylthiazol-2-yl]-2,5 diphenyl tetrazolium bromide) assay was used to detect hLEC viability. HLECs were divided into Blank, H2O2, mimics (miRNA-124 mimics) + H2O2, NC+ H2O2, pyrrolidine dithiocarbamate (PDTC; NF-κB signaling pathway inhibitor) + H2O2, and inhibitors (miRNA-124 inhibitors) + PDTC + H2O2 groups. Quantitative real-time polymerase chain reaction and Western blot were employed to detect mRNA and protein expressions, Dichloro-dihydro-fluorescein diacetate to measure reactive oxygen species (ROS) production, and AnnexinV-FITC/PI staining to determine cell apoptosis. The mitochondrial membrane potential (MMP) was detected by fluorescence probe JC-1. Results: The H2O2-induced hLEC showed reductions in cell viability with decreased miRNA-124 but increased p-p65 in a dose-/time-dependent manner. Furthermore, ROS production, malondialdehyde content, Bax and Caspase-3 expressions, and cell apoptosis were elevated in H2O2-induced hLEC, whereas the activities of superoxide dismutase and glutathione peroxidase, Bcl-2 expression, MMP, as well as the mitochondrial energy metabolism genes were reduced. Additionally, miRNA-124 mimics and PDTC both decreased the p-p65 and reversed the cytotoxicity in H2O2-induced hLEC. Conclusion: MiRNA-124 prevents H2O2-induced oxidative stress and apoptosis in hLEC through suppressing the activation of the NF-κB pathway.

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Suppressive Effects of Rosmarinic Acid Rich Fraction from Perilla on Oxidative Stress, Inflammation and Metastasis Ability in A549 Cells Exposed to PM via C-Jun, P-65-Nf-Κb and Akt Signaling Pathways

Biomolecules ◽

10.3390/biom11081090 ◽

2021 ◽

Vol 11 (8) ◽

pp. 1090

Author(s):

Komsak Pintha ◽

Wittaya Chaiwangyen ◽

Supachai Yodkeeree ◽

Maitree Suttajit ◽

Payungsak Tantipaiboonwong

Keyword(s):

Oxidative Stress ◽

Signaling Pathways ◽

Rosmarinic Acid ◽

Molecular Mechanisms ◽

Cancer Metastasis ◽

A549 Cells ◽

Akt Signaling ◽

Seed Meal ◽

Ros Production ◽

Perilla Seed

Particulate matter from forest fires (PMFF) is an environmental pollutant causing oxidative stress, inflammation, and cancer cell metastasis due to the presence of polycyclic aromatic hydrocarbons (PAHs). Perilla seed meal contains high levels of polyphenols, including rosmarinic acid (RA). The aim of this study is to determine the anti-oxidative stress, anti-inflammation, and anti-metastasis actions of rosmarinic acid rich fraction (RA-RF) from perilla seed meal and its underlying molecular mechanisms in A549 cells exposed to PMFF. PMFF samples were collected via the air sampler at the University of Phayao, Thailand, and their PAH content were analyzed using GC-MS. Fifteen PAH compounds were detected in PMFF. The PMFF significantly induced intracellular reactive oxygen species (ROS) production, the mRNA expression of pro-inflammatory cytokines, MMP-9 activity, invasion, migration, the overexpression of c-Jun and p-65-NF-κB, and Akt phosphorylation. Additionally, the RA-RF significantly reduced ROS production, IL-6, IL-8, TNF-α, and COX-2. RA-RF could also suppress MMP-9 activity, migration, invasion, and the phosphorylation activity of c-Jun, p-65-NF-κB, and Akt. Our findings revealed that RA-RF has antioxidant, anti-inflammatory, and anti-metastasis properties via c-Jun, p-65-NF-κB, and Akt signaling pathways. RA-RF may be further developed as an inhalation agent for the prevention of lung inflammation and cancer metastasis induced by PM exposure.

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Rehmanniae Decoction Improve Brain Function in Vascular Dementia Rats Through Phosphoinositide 3-Kinase (PI3K)/AKT Signaling Pathway

Journal of Biomaterials and Tissue Engineering ◽

10.1166/jbt.2020.2286 ◽

2020 ◽

Vol 10 (4) ◽

pp. 538-544

Author(s):

Peng Sang ◽

Jiahui Zhao ◽

Shun Wang ◽

Hui Yang ◽

Huijuan Shi

Keyword(s):

Oxidative Stress ◽

Learning And Memory ◽

Cell Apoptosis ◽

Caspase 3 ◽

Sham Group ◽

Akt Signaling ◽

Sod Activity ◽

Memory Ability ◽

Group I ◽

Mda Content

Objective: Studies have shown that Rehmanniae Decoction (Reh) has therapeutic effect on vascular dementia (VD). PI3K/AKT signaling regulates oxidative stress damage and cell apoptosis. Our study intends torehmanniae decoction's effect on the neural function in VD mice. Methods: The mice were divided into Sham group, VD group, low dose Reh+ VD group and high dose Reh+ VD group. Water maze test was used to assess learning and memory ability. The activity of caspase-3, the content of MDA and the activity of SOD enzyme in hippocampus were detected. In vitro , HT22 cells were divided into control group, I–R group, I–R+ 2% Reh serum, I–R+ 4% Reh serum. Flow cytometry was used to detect the intracellular content of ROS and cell apoptosis. Results: Compared with sham group, the learning and memory ability of mice in VD group was significantly decreased. p-AKT level and SOD activity in the hippocampus was decreased, the Caspase-3 activity and MDA content was significantly increased. After treatment of Reh, the learning and memory ability of VD model mice was significantly improved, p-AKT protein expression and SOD activity were up-regulated, and Caspase-3 activity and MDA content were reduced. Conclusion: Rehmanniae decoction alleviates the oxidative stress and inhibits cell apoptosis to improve the function of brain by regulating PI3K/AKT pathway.

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SIRT1 Suppresses Doxorubicin-Induced Cardiotoxicity by Regulating the Oxidative Stress and p38MAPK Pathways

Cellular Physiology and Biochemistry ◽

10.1159/000373937 ◽

2015 ◽

Vol 35 (3) ◽

pp. 1116-1124 ◽

Cited By ~ 40

Author(s):

Yang Ruan ◽

Chunlin Dong ◽

Jigar Patel ◽

Chao Duan ◽

Xinyue Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Heart Failure ◽

Cell Survival ◽

Cell Apoptosis ◽

Heart Function ◽

Cardiomyocyte Apoptosis ◽

Neonatal Rat ◽

Signal Pathways ◽

Ros Production ◽

Sirt1 Expression

Background: SIRT1, which belongs to the Sirtuin family of NAD-dependent enzymes, plays diverse roles in aging, metabolism, and disease biology. It could regulate cell survival and has been shown to be a protective factor in heart function. Hence, we verified the mechanism by which SIRT1 regulates doxorubicin induced cardiomyocyte injury in vivo and in vitro. Methods: We analyzed SIRT1 expression in doxorubicin-induced neonatal rat cardiomyocyte injury model and adult mouse heart failure model. SIRT1 was over-expressed in cultured neonatal rat cardiomyocyte by adenovirus mediated gene transfer. SIRT1 agonist resveratrol was used to treat the doxorubicin-induced heart failure mouse model. Echocardiography, reactive oxygen species (ROS) production, TUNEL, qRT-PCR, and Western blotting were performed to analyze cell survival, oxidative stress, and inflammatory signal pathways in cardiomyocytes. Results: SIRT1 expression was down-regulated in doxorubicin induced cardiomocyte injury, accompanied by elevated oxidative stress and cell apoptosis. SIRT1 over-expression reduced doxorubicin induced cardiomyocyte apoptosis with the attenuated ROS production. SIRT1 also reduced cell apoptosis by inhibition of p38MAPK phosphorylation and caspase-3 activation. The SIRT1 agonist resveratrol was able to prevent doxorubicin-induced heart function loss. Moreover, the SIRT1 inhibitor niacinamide could reverse SIRT1's protective effect in cultured neonatal rat cardiomyocytes. Conclusions: These results support the role of SIRT1 as an important regulator of cardiomyocyte apoptosis during doxorubicin-induced heart injury, which may represent a potential therapeutic target for doxorubicin-induced cardiomyopathy.

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Epigallocatechin-3-Gallate Attenuates Adriamycin-Induced Focal Segmental Glomerulosclerosis via Suppression of Oxidant Stress and Apoptosis by Targeting Hypoxia-Inducible Factor-1α/ Angiopoietin-Like 4 Pathway

Pharmacology ◽

10.1159/000496799 ◽

2019 ◽

Vol 103 (5-6) ◽

pp. 303-314 ◽

Cited By ~ 1

Author(s):

Guoyong Liu ◽

Liyu He

Keyword(s):

Body Weight ◽

Cell Apoptosis ◽

Caspase 3 ◽

Oxidant Stress ◽

Hypoxia Inducible Factor ◽

Control Group ◽

Tunel Staining ◽

Ros Production ◽

Egcg Treatment ◽

Hypoxia Inducible Factor 1Α

Background: Focal and segmental glomerular sclerosis (FSGS) is a common cause of nephrotic syndrome and end-stage renal disease. It has been reported that overproduction of reactive oxygen species (ROS) and cell apoptosis are associated with the development of FSGS. Epigallocatechin-3-gallate (EGCG) is a bioactive constituent accounting for more than 50% of the total catechins in green tea, which have anti-oxidative and anti-apoptotic effects. Based on this, this study was designed to evaluate the renoprotective effect of EGCG treatment on Adriamycin-induced FSGS. Methods: In C57BL/6 mice, Adriamycin nephropathy (AN) was induced by Adriamycin (10 mg/kg body weight, diluted in normal saline) via a tail vein on day 0. Then the mice were given with EGCG (20 mg/kg body weight) or YC-1 (Lificiguat, a specific inhibitor of hypoxia-inducible factor-1α [HIF-1α], 50 mg/kg body weight) or both intraperitoneally. Both the EGCG and YC-1 were given on the day of Adriamycin injection and continued for 6 weeks. The animals were organized into the following 5 groups for the animal experiments: the control group, the AN group, the AN + EGCG group, the AN + YC-1 group and the AN + EGCG + YC-1 group. At 6 weeks, the mice were sacrificed; kidneys and blood samples were collected for further analysis. The HIF-1α and the angiopoietin-like 4 (ANGPTL4) expression were detected by Western blot, real-time PCR, immunohistochemistry or immunofluorescence. Dihydroethidium staining and NADPH oxidase 1 (Nox1) measurement were used to detect ROS production. Terminal deoxynucleotide transferase-mediated dUTP nick end-labeling (TUNEL) staining and caspase-3 measurement was used to detect cell apoptosis. Results: When the animals were treated with Adriamycin, both the ROS production and TUNEL positive cells increased. Besides, the expression of HIF-1α, ANGPTL4, and caspase-3 were also up-regulated, while EGCG treatment could attenuate these changes. Interestingly, compared with treatment with YC-1 or EGCG alone, more pronounced inhibition of ANGPTL4, caspase-3 and Nox1 were obtained when YC-1 and EGCG were administered simultaneously. Conclusion: EGCG attenuates FSGS through the suppression of Oxidant Stress and apoptosis by targeting the HIF-1α/ANGPTL4 pathway.

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