Insulin alleviates mitochondrial oxidative stress involving upregulation of superoxide dismutase 2 and uncoupling protein 2 in septic acute kidney injury

Many studies proposed that oxidative stress and apoptosis are key mechanisms in the pathogenesis of contrast-induced acute kidney injury (CI-AKI). Xylose-pyrogallol conjugate (XP) is an original effective antioxidant that showed decent antioxidant and anti-apoptosis effect before. Thus the therapeutic effect and mechanism of XP in preventing CI-AKI in the short and long term were investigated in this research. Renal function and histological grade were evaluated to determine the severity of renal injury. Kidney samples were then collected for the measurement of oxidative stress markers and the detection of apoptosis. Transmission electron microscopy (TEM) and western blot of mitochondrial protein were utilized for the analysis of the mitochondrial conditions. The results demonstrated that the CI-AKI rats caused a significant decrease in renal function accompanied by a remarkable increase in Malondialdehyde (MDA), bax, caspase-3, cytochrome c (Cyt C) level, TdT-mediated dUTP nick end labeling (TUNEL) positive apoptotic cells, and damaged mitochondria, while a decline in antioxidase activities and mitochondrial superoxide dismutase 2 (SOD2) expression compared with the control rats. However, when XP (50 or 100 or 200 mg/kg/day) was given orally for consecutive 7 days before CI-AKI modeling, XP (200 mg/kg) showed a better capability to restore renal dysfunction, histopathological appearance, the level of apoptosis, mitochondrial damage, oxidative stress, and fibrosis generation without interference in computed tomographic imaging. Our study indicated that antioxidant XP played a nephroprotective role probably via antiapoptotic and antioxidant mechanisms. Besides, XP may regulate the mitochondria pathway via decreasing the ratio of bax/bcl-2, inhibiting caspase-3 expression, cytochrome c release, and superoxide dismutase 2 activity. Overall, XP as a high-efficient antioxidant may have the potentials to prevent CI-AKI.

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The Warburg Effect Promotes Mitochondrial Injury Regulated by Uncoupling Protein-2 in Septic Acute Kidney Injury

Shock ◽

10.1097/shk.0000000000001576 ◽

2020 ◽

Vol Publish Ahead of Print ◽

Cited By ~ 1

Author(s):

Ran Ji ◽

Weiwei Chen ◽

Yuming Wang ◽

Fangchen Gong ◽

Shunwei Huang ◽

...

Keyword(s):

Acute Kidney Injury ◽

Warburg Effect ◽

Uncoupling Protein ◽

Kidney Injury ◽

Uncoupling Protein 2 ◽

Mitochondrial Injury ◽

Septic Acute Kidney Injury ◽

The Warburg Effect

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The Effect of Superoxide Dismutase on Inhibition of Acute Kidney Injury Induced by Sepsis Based on Kidney Tissue Histology and Murine Sepsis Score

The Scientific World JOURNAL ◽

10.1155/2021/1827296 ◽

2021 ◽

Vol 2021 ◽

pp. 1-7

Author(s):

Jufitriani Ismy ◽

Maimun Syukri ◽

Dessy R. Emril ◽

Nanan Sekarwana ◽

Jufriady Ismy ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Superoxide Dismutase ◽

Kidney Tissue ◽

Kidney Injury ◽

Male Rats ◽

Control Group ◽

Control Group Design ◽

Group I ◽

Sepsis Score

Sepsis is one of the leading causes contributing to the incidence of acute kidney injury (AKI). Oxidative stress can be used as the main approach against sepsis-induced AKI. One of the primary antioxidants that plays a role in warding off oxidative stress is superoxide dismutase (SOD). This research aimed to observe the effect of antioxidant SOD in inhibiting sepsis in AKI based on kidney tissue histopathology. The research method was an experimental laboratory with a post-test-only control group design. Twenty-five adult male rats aged 12–16 weeks, weighing between 200 and 250 g, were randomly divided into five groups: Group I, as a positive control, where rats were injected with lipopolysaccharides (LPS); Group II, as a negative control; Group III, as treatment 1, where rats were injected with LPS and administered orally with SOD (Glisodin®) 250 IU daily; Group IV, as treatment 2, where rats were injected with LPS and administered orally with SOD (Glisodin®) 500 IU daily; and Group V, as treatment 2, where rats were injected with LPS and administered orally with SOD (Glisodin®) 1000 IU daily. Rats were administered with SOD (Glisodin®) by oral gavage with a flexible feeding tube for 16 weeks, given once daily in the morning, and then injected with LPS of 10 mg/kg body weight. Glisodin SOD had a significant effect on murine sepsis score (MSS). MSS influenced the tubular injury score linearly. We conclude that the optimal dose of SOD at 1000 IU for inhibiting sepsis-induced AKI incidence is compared to SOD at a dose of 250 and 500 IU. The antioxidant effect of SOD can prevent sepsis-induced AKI with oxidative stress events.

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Inducible HSP70 regulates superoxide dismutase-2 and mitochondrial oxidative stress in the endothelial cells from developing lungs

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00264.2013 ◽

2014 ◽

Vol 306 (4) ◽

pp. L351-L360 ◽

Cited By ~ 28

Author(s):

Adeleye J. Afolayan ◽

Ru-Jeng Teng ◽

Annie Eis ◽

Ujala Rana ◽

Katarzyna A. Broniowska ◽

...

Keyword(s):

Oxidative Stress ◽

Endothelial Cells ◽

Superoxide Dismutase ◽

Specific Inhibitor ◽

Cellular Respiration ◽

Relaxation Response ◽

Mitochondrial Atpase ◽

Mitochondrial Oxidative Stress ◽

Atp Levels ◽

Superoxide Dismutase 2

Superoxide dismutase 2 (SOD-2) is synthesized in the cytosol and imported into the mitochondrial matrix, where it is activated and functions as the primary antioxidant for cellular respiration. The specific mechanisms that target SOD-2 to the mitochondria remain unclear. We hypothesize that inducible heat shock protein 70 (iHSP70) targets SOD-2 to the mitochondria via a mechanism facilitated by ATP, and this process is impaired in persistent pulmonary hypertension of the newborn (PPHN). We observed that iHSP70 interacts with SOD-2 and targets SOD-2 to the mitochondria. Interruption of iHSP70-SOD-2 interaction with 2-phenylethylenesulfonamide-μ (PFT-μ, a specific inhibitor of substrate binding to iHSP70 COOH terminus) and siRNA-mediated knockdown of iHSP70 expression disrupted SOD-2 transport to mitochondria. Increasing intracellular ATP levels by stimulation of respiration with CaCl2 facilitated the mitochondrial import of SOD-2, increased SOD-2 activity, and decreased the mitochondrial superoxide (O2·−) levels in PPHN pulmonary artery endothelial cells (PAEC) by promoting iHSP70-SOD-2 dissociation at the outer mitochondrial membrane. In contrast, oligomycin, an inhibitor of mitochondrial ATPase, decreased SOD-2 expression and activity and increased O2·− levels in the mitochondria of control PAEC. The basal ATP levels and degree of iHSP70-SOD-2 dissociation were lower in PPHN PAEC and lead to increased SOD-2 degradation in cytosol. In normal pulmonary arteries (PA), PFT-μ impaired the relaxation response of PA rings in response to nitric oxide (NO) donor, S-nitroso- N-acetyl-penicillamine. Pretreatment with Mito-Q, a mitochondrial targeted O2·− scavenger, restored the relaxation response in PA rings pretreated with PFT-μ. Our observations suggest that iHSP70 chaperones SOD-2 to the mitochondria. Impaired SOD-2-iHSP70 dissociation decreases SOD-2 import and contributes to mitochondrial oxidative stress in PPHN.

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Increased Plasma Manganese, Partially Reduced Ascorbate,1 and Absence of Mitochondrial Oxidative Stress in Type 2 Diabetes Mellitus: Implications for the Superoxide Uncoupling Protein 2 (Ucp-2) Pathway

Biological Trace Element Research ◽

10.1007/s12011-007-0069-x ◽

2007 ◽

Vol 120 (1-3) ◽

pp. 19-27 ◽

Cited By ~ 7

Author(s):

J. I. Anetor ◽

O. A. Asiribo ◽

K. S. Adedapo ◽

T. S. Akingbola ◽

O. S. Olorunnisola ◽

...

Keyword(s):

Oxidative Stress ◽

Diabetes Mellitus ◽

Type 2 Diabetes ◽

Type 2 Diabetes Mellitus ◽

Uncoupling Protein ◽

Uncoupling Protein 2 ◽

Mitochondrial Oxidative Stress

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Erythrocyte superoxide dismutase as a biomarker of septic acute kidney injury

Annals of Intensive Care ◽

10.1186/s13613-016-0198-5 ◽

2016 ◽

Vol 6 (1) ◽

Cited By ~ 12

Author(s):

Nara Aline Costa ◽

Ana Lúcia Gut ◽

Paula Schmidt Azevedo ◽

Suzana Erico Tanni ◽

Natália Baraldi Cunha ◽

...

Keyword(s):

Acute Kidney Injury ◽

Superoxide Dismutase ◽

Kidney Injury ◽

Septic Acute Kidney Injury ◽

Erythrocyte Superoxide Dismutase

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Knockdown of circ-FANCA alleviates LPS-induced HK2 cell injury via targeting miR-93-5p/OXSR1 axis in septic acute kidney injury

Diabetology & Metabolic Syndrome ◽

10.1186/s13098-021-00625-8 ◽

2021 ◽

Vol 13 (1) ◽

Author(s):

Heyun Li ◽

Xia Zhang ◽

Peng Wang ◽

Xiaoyan Zhou ◽

Haiying Liang ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Cell Injury ◽

Kidney Injury ◽

Cell Counting ◽

Luciferase Reporter ◽

Enzyme Linked Immunosorbent Assay ◽

Septic Acute Kidney Injury ◽

Hk2 Cells ◽

And Oxidative Stress

Abstract Background Sepsis is life-threatening disease with systemic inflammation and can lead to various diseases, including septic acute kidney injury (AKI). Recently, diverse circular RNAs (circRNAs) are considered to be involved in the development of this disease. In this study, we aimed to elucidate the role of circ-FANCA and the potential action mechanism in sepsis-induced AKI. Methods HK2 cells were treated with lipopolysaccharide (LPS) to establish septic AKI cell model. The expression of circ-FANCA, microRNA-93-5p (miR-93-5p) and oxidative stress responsive 1 (OXSR1) mRNA was determined by quantitative real-time polymerase chain reaction (qRT-PCR). Cell viability was assessed using cell counting kit-8 (CCK-8) assay. Cell apoptosis and cell cycle distribution were measured by flow cytometry. The inflammatory response was monitored according to the release of pro-inflammatory cytokines via enzyme-linked immunosorbent assay (ELISA). The activities of oxidative indicators were examined using the corresponding kits. Dual-luciferase reporter assay and RNA immunoprecipitation (RIP) assay were applied to validate the interaction between miR-93-5p and circ-FANCA or OXSR1. Protein analysis was conducted through western blot. Results Circ-FANCA was upregulated in septic AKI serum specimens and LPS-treated HK2 cells. Functionally, circ-FANCA knockdown facilitated cell proliferation and restrained apoptosis, inflammation and oxidative stress in LPS-triggered HK2 cells. Further mechanism analysis revealed that miR-93-5p was a target of circ-FANCA and circ-FANCA modulated LPS-induced cell damage by targeting miR-93-5p. Meanwhile, miR-93-5p overexpression repressed LPS-treated HK2 cell injury by sponging OXSR1. Furthermore, circ-FANCA regulated OXSR1 expression by sponging miR-93-5p. Besides, exosome-derived circ-FANCA was upregulated in LPS-induced HK2 cells, which was downregulated by GW4869. Conclusion Circ-FANCA knockdown attenuated LPS-induced HK2 cell injury by regulating OXSR1 expression via targeting miR-93-5p.

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Targeting Oxidative Stress in Septic Acute Kidney Injury: From Theory to Practice

Journal of Clinical Medicine ◽

10.3390/jcm10173798 ◽

2021 ◽

Vol 10 (17) ◽

pp. 3798

Author(s):

Connie P. C. Ow ◽

Anton Trask-Marino ◽

Ashenafi H. Betrie ◽

Roger G. Evans ◽

Clive N. May ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Reactive Nitrogen Species ◽

Kidney Injury ◽

Oxygen Species ◽

Clinical Sepsis ◽

Human Sepsis ◽

Theory To Practice ◽

Septic Acute Kidney Injury ◽

Pleiotropic Actions

Sepsis is the leading cause of acute kidney injury (AKI) and leads to increased morbidity and mortality in intensive care units. Current treatments for septic AKI are largely supportive and are not targeted towards its pathophysiology. Sepsis is commonly characterized by systemic inflammation and increased production of reactive oxygen species (ROS), particularly superoxide. Concomitantly released nitric oxide (NO) then reacts with superoxide, leading to the formation of reactive nitrogen species (RNS), predominantly peroxynitrite. Sepsis-induced ROS and RNS can reduce the bioavailability of NO, mediating renal microcirculatory abnormalities, localized tissue hypoxia and mitochondrial dysfunction, thereby initiating a propagating cycle of cellular injury culminating in AKI. In this review, we discuss the various sources of ROS during sepsis and their pathophysiological interactions with the immune system, microcirculation and mitochondria that can lead to the development of AKI. We also discuss the therapeutic utility of N-acetylcysteine and potential reasons for its efficacy in animal models of sepsis, and its inefficacy in ameliorating oxidative stress-induced organ dysfunction in human sepsis. Finally, we review the pre-clinical studies examining the antioxidant and pleiotropic actions of vitamin C that may be of benefit for mitigating septic AKI, including future implications for clinical sepsis.

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LncRNA-UCA1 Alleviates Septic Acute Kidney Injury through Regulating Endoplasmic Reticulum Stress in LPS-treated HK-2 Cells

10.1101/2021.04.06.438568 ◽

2021 ◽

Author(s):

TT Yu ◽

FL Cai ◽

J Niu

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Endoplasmic Reticulum ◽

Er Stress ◽

Noncoding Rna ◽

Kidney Injury ◽

Tunel Staining ◽

Septic Acute Kidney Injury ◽

Commercial Kits

AbstractObjectiveSeptic acute kidney injury (AKI) is an important cause of death in patients with sepsis. This study sought to explore the function of the long noncoding RNA, urothelial carcinoma associated 1 (lncRNA-UCA1), in septic AKI and determine the underlying molecular mechanism.MethodsHK-2 cells were treated with lipopolysaccharide (LPS) to establish an in vitro model of septic AKI. Quantitative reverse-transcription polymerase chain reaction (qRT-PCR) was used to detect the expression of lncRNA-UCA1. CCK-8 assay was used to detect the viability of HK-2 cells. Western blotting was utilized to examine protein expression. The contents of SOD, GSH, MDA, and ROS were determined using commercial kits. The apoptosis rate was calculated using TUNEL staining and flow cytometry.ResultsLncRNA-UCA1 was down-regulated in LPS-treated HK-2 cells. LPS significantly reduced the content of SOD and GSH in HK-2 cells, increased the production of MDA and ROS, and led to an increase in the rate of apoptosis. However, overexpression of lncRNA-UCA1 protected HK-2 cells from oxidative stress and apoptosis. Furthermore, LPS induced endoplasmic reticulum (ER) stress in HK-2 cells, which was inhibited by overexpression of lncRNA-UCA1.ConclusionOverexpression of lncRNA-UCA1 inhibited LPS-induced oxidative stress and apoptosis of HK-2 cells by suppressing ER stress.

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