Fish oils protects against cecal ligation and puncture‑induced septic acute kidney injury via the regulation of inflammation, oxidative stress and apoptosis

Sepsis is a systemic response to infections that may culminate into a life-threatening syndrome, the most common cause of acute kidney injury. Despite increasing mortality associated with septic acute kidney injury, its pathogenesis is poorly understood resulting in limited treatment options. Amygdalin participates in the regulation of various signaling pathways including Janus kinase/signal transducer and activator of transcription 3 signaling pathway. This pathway is critical for initiating immune responses and controlling persistent inflammation in various conditions such as infection. Cecal ligation and puncture is a most frequently used method for modeling sepsis. In the rat cecal ligation and puncture model, the levels of serum creatinine and blood urea nitrogen, as well as the serum levels of proinflammatory cytokines (tumor necrosis factor-α, interleukin-6, and interleukin-18) are significantly elevated. Furthermore, cecal ligation and puncture promotes cell apoptosis with increased BCL2-associated X protein and reduced B-cell lymphoma 2 protein expression. In this study, we have observed amygdalin to reduce serum cytokine secretion and prevent renal cell apoptosis in kidney injury, thus ameliorate kidney injury. The protective role of amygdalin in septic acute kidney injury was mediated through inhibition of Janus kinase/signal transducer and activator of the transcription 3 signaling pathway.

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Platycodin D Ameliorates Acute Kidney Injury in Septic Rats by Regulating Mitogen Activated Protein Kinase Pathway

Current Topics in Nutraceutical Research ◽

10.37290/ctnr2641-452x.19:270-276 ◽

2020 ◽

Vol 19 (3) ◽

pp. 270-276

Author(s):

Jianying Wang ◽

Xiaoting Yu

Keyword(s):

Acute Kidney Injury ◽

Protein Kinase ◽

Protective Effect ◽

Cecal Ligation ◽

Kidney Injury ◽

B Cell Lymphoma ◽

Mitogen Activated Protein Kinase ◽

Cecal Ligation And Puncture ◽

Platycodin D ◽

Mitogen Activated Protein

Acute kidney injury is a severe complication of sepsis. We have shown a protective effect of Platycodin D on sepsis induced acute kidney injury in an animal model that employs cecal ligation and puncture. Cecal ligation and puncture induced a series of degenerative changes in kidney, such as edema, hyperemia, and expansion in glomerular capillary, and inflammatory cells infiltration that were attenuated by Platycodin D. Also, rise in proinflammatory cytokine levels in septic rats was blunted by Platycodin D. Furthermore, Platycodin D administration reduced rise in serum levels of kidney injury markers-blood urea nitrogen and serum creatinine-in septic rats. Moreover, Platycodin D administration also suppressed the cell apoptosis in kidney that was associated with enhanced B-cell lymphoma 2 protein and reduced cleaved cysteine-aspartic protease-3 and BCL2-associated X protein. Lastly, Platycodin D administration attenuated sepsis-induced increase of phospho (p)-extracellular signal-regulated kinase, p-c-Jun NH2-terminal kinase, and p-p38. In conclusion, Platycodin D demonstrated protective effect against sepsis induced acute kidney injury through inactivation of mitogen activated protein kinase pathways, thus providing promising therapeutic strategy for the treatment of sepsis.

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Sepsis-induced acute kidney injury: kidney protection effects by antioxidants

Revista Brasileira de Enfermagem ◽

10.1590/0034-7167-2017-0469 ◽

2018 ◽

Vol 71 (4) ◽

pp. 1921-1927 ◽

Cited By ~ 5

Author(s):

Carolina Ferreira Vasco ◽

Mirian Watanabe ◽

Cassiane Dezoti da Fonseca ◽

Maria de Fátima Fernandes Vattimo

Keyword(s):

Blood Pressure ◽

Acute Kidney Injury ◽

Creatinine Clearance ◽

Experimental Model ◽

Kidney Function ◽

Cecal Ligation ◽

Kidney Injury ◽

Cecal Ligation And Puncture ◽

Antioxidant Action ◽

Average Blood Pressure

ABSTRACT Objective: To evaluate the antioxidant action of N-acetylcysteine and diosmin-hesperidin in an experimental model of sepsis-induced acute kidney injury in rats. Methods: The study used 20 Wistar adult male rats divided into the following groups: control (laparotomy with no induction of abdominal sepsis), sepsis (experimental model of sepsis with cecal ligation and puncture), N-acetylcysteine + sepsis and diosmin-hesperidin + sepsis. The evaluation contemplated physiological parameters (temperature, glycemia, and average blood pressure), kidney function (creatinine clearance), oxidative stress (urinary peroxides) and kidney histology. Results: The animals submitted to cecal ligation and puncture (sepsis) presented lower body temperature, lower average blood pressure, reduced creatinine clearance and increased urinary hydrogen peroxide levels. Treatment with diosmin-hesperidin improved kidney function and led to a reduction in the excretion of oxidative metabolites. Conclusion: The present study highlighted the protective antioxidant action of diosmin-hesperidin in the experimental model of sepsis-induced acute kidney injury.

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IL-17A activated by Toll-like receptor 9 contributes to the development of septic acute kidney injury

AJP Renal Physiology ◽

10.1152/ajprenal.00313.2019 ◽

2020 ◽

Vol 318 (1) ◽

pp. F238-F247

Author(s):

Yoshitaka Naito ◽

Takayuki Tsuji ◽

Soichiro Nagata ◽

Naoko Tsuji ◽

Tomoyuki Fujikura ◽

...

Keyword(s):

Acute Kidney Injury ◽

Critical Role ◽

Cecal Ligation ◽

Kidney Injury ◽

Mrna Levels ◽

Toll Like Receptor ◽

Γδt Cells ◽

Morphological Aspects ◽

Septic Acute Kidney Injury

Toll-like receptor 9 (TLR9), which is activated by endogenously released mtDNA during sepsis, contributes to the development of polymicrobial septic acute kidney injury (AKI). However, downstream factors of TLR9 to AKI remain unknown. We hypothesized that IL-17A activated by TLR9 may play a critical role in septic AKI development. To determine the effects of TLR9 on IL-17A production in septic AKI, we used a cecal ligation and puncture (CLP) model in Tlr9 knockout ( Tlr9KO) mice and wild-type (WT) littermates. We also investigated the pathway from TLR9 activation in dendritic cells (DCs) to IL-17A production by γδT cells in vitro. To elucidate the effects of IL-17A on septic AKI, Il-17a knockout ( Il-17aKO) mice and WT littermates were subjected to CLP. We further investigated the relationship between the TLR9-IL-17A axis and septic AKI by intravenously administering recombinant IL-17A or vehicle into Tlr9KO mice and assessing kidney function. IL-17A levels in both plasma and the peritoneal cavity and mRNA levels of IL-23 in the spleen were significantly higher in WT mice after CLP than in Tlr9KO mice. Bone marrow-derived DCs activated by TLR9 induced IL-23 and consequently promoted IL-17A production in γδT cells in vitro. Knockout of Il-17a improved survival, functional and morphological aspects of AKI, and splenic apoptosis after CLP. Exogenous IL-17A administration aggravated CLP-induced AKI attenuated by knockout of Tlr9. TLR9 in DCs mediated IL-17A production in γδT cells during sepsis and contributed to the development of septic AKI.

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SIRT1/3 Activation by Resveratrol Attenuates Acute Kidney Injury in a Septic Rat Model

Oxidative Medicine and Cellular Longevity ◽

10.1155/2016/7296092 ◽

2016 ◽

Vol 2016 ◽

pp. 1-12 ◽

Cited By ~ 34

Author(s):

Siqi Xu ◽

Youguang Gao ◽

Qin Zhang ◽

Siwei Wei ◽

Zhongqing Chen ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Survival Time ◽

Rat Model ◽

Cecal Ligation ◽

Kidney Tissue ◽

Kidney Injury ◽

Tubular Epithelial Cell ◽

Multiple Organ ◽

Organ Systems

Sepsis often results in damage to multiple organ systems, possibly due to severe mitochondrial dysfunction. Two members of the sirtuin family, SIRT1 and SIRT3, have been implicated in the reversal of mitochondrial damage. The aim of this study was to determine the role of SIRT1/3 in acute kidney injury (AKI) following sepsis in a septic rat model. After drug pretreatment and cecal ligation and puncture (CLP) model reproduction in the rats, we performed survival time evaluation and kidney tissue extraction and renal tubular epithelial cell (RTEC) isolation. We observed reduced SIRT1/3 activity, elevated acetylated SOD2 (ac-SOD2) levels and oxidative stress, and damaged mitochondria in RTECs following sepsis. Treatment with resveratrol (RSV), a chemical SIRT1 activator, effectively restored SIRT1/3 activity, reduced acetylated SOD2 levels, ameliorated oxidative stress and mitochondrial function of RTECs, and prolonged survival time. However, the beneficial effects of RSV were greatly abrogated by Ex527, a selective inhibitor of SIRT1. These results suggest a therapeutic role for SIRT1 in the reversal of AKI in septic rat, which may rely on SIRT3-mediated deacetylation of SOD2. SIRT1/3 activation could therefore be a promising therapeutic strategy to treat sepsis-associated AKI.

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Circular RNA TLK1 Promotes Sepsis-Associated Acute Kidney Injury by Regulating Inflammation and Oxidative Stress Through miR-106a-5p/HMGB1 Axis

Frontiers in Molecular Biosciences ◽

10.3389/fmolb.2021.660269 ◽

2021 ◽

Vol 8 ◽

Author(s):

Hai-Ping Xu ◽

Xiao-Ying Ma ◽

Chen Yang

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Rat Model ◽

Cecal Ligation ◽

Kidney Injury ◽

Serum Levels ◽

Circular Rnas ◽

Inflammatory Disorder ◽

Oxidation Stress ◽

And Oxidative Stress

Sepsis is an inflammatory disorder and leads to severe acute kidney injury (AKI). Circular RNAs (circRNAs) have been identified as a critical type of regulatory noncoding RNAs (ncRNAs) that present the important functions in various diseases. In this study, we identified a novel circRNA circTLK1 in the regulation of sepsis-induced AKI. We observed that circTLK1 expression was elevated in the cecal ligation and puncture (CLP) rat model compared with that in the control rats. The urine levels of neutrophil gelatinase–associated lipocalin (NGAL) and kidney injury molecule-1 (Kim-1) and the serum levels of creatinine (sCr) and blood urea nitrogen (BUN) were increased by the CLP treatment in the rats but were blocked by the circTLK1 shRNA. The circTLK1 shRNA reduced the CLP-induced kidney injury in the rats. The circTLK1 knockdown repressed oxidation stress, inflammation, and apoptosis in the sepsis-related AKI rat model. Moreover, lipopolysaccharide (LPS) treatment increased the production of TNF-α, IL-1β, and IL-6 in the HK-2 cells, while the circTLK1 shRNA could attenuate the enhancement in the cells. Bax and cleaved caspase-3 expression was upregulated, but Bcl-2 expression was downregulated by the LPS in the HK-2 cells, in which circTLK1 depletion reversed this effect in the cells. The depletion of circTLK1 attenuated the LPS-induced apoptosis in the HK-2 cells. CircTLK1 enhanced HMGB1 expression by sponging miR-106a-5p in the HK-2 cells, and miR-106a-5p and HMGB1 were involved in circTLK1-meidated injury of LPS-treated cells. Therefore, we concluded that circTLK1 contributed to sepsis-associated AKI by regulating inflammation and oxidative stress through the miR-106a-5p/HMGB1 axis. CircTLK1 and miR-106a-5p may be employed as the potential targets for the treatment of AKI.

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Upregulation of lncRNA NONRATG019935.2 suppresses the p53-mediated apoptosis of renal tubular epithelial cells in septic acute kidney injury

Cell Death and Disease ◽

10.1038/s41419-021-03953-9 ◽

2021 ◽

Vol 12 (8) ◽

Author(s):

Ying Ding ◽

Dao-yang Zhou ◽

Hong Yu ◽

Tao Zhu ◽

Feng Guo ◽

...

Keyword(s):

Acute Kidney Injury ◽

Epithelial Cells ◽

Rat Model ◽

Mrna Stability ◽

Cecal Ligation ◽

Kidney Injury ◽

Tubular Epithelial Cells ◽

Renal Tubular Epithelial Cells ◽

Septic Acute Kidney Injury ◽

Renal Tubular

AbstractAlthough increasing evidence has confirmed that the apoptosis of renal tubular epithelial cells (RTECs) is a crucial contributor to the onset and development of septic acute kidney injury (AKI), the pathological mechanism by which RTEC apoptosis is upregulated during septic AKI is not entirely clear. In this study, a rat model of septic AKI was induced by a cecal ligation puncture procedure or lipopolysaccharide (LPS) injection. Four differentially expressed long noncoding RNAs (DE-Lncs) in the rat model of septic AKI were determined using RNA-sequencing and verified by qRT-PCR. Among the four DE-Lncs, the expression level of lncRNA NONRATG019935.2 (9935) exhibited the most significant reduction in both septic AKI rats and LPS-treated NRK-52E cells (a rat RTEC line). The overexpression of 9935 suppressed cell apoptosis and p53 protein level in LPS-treated NRK-52E cells, and retarded septic AKI development in the rat model of septic AKI. Mechanistically, 9935 decreased the human antigen R (HuR)-mediated Tp53 mRNA stability by limiting the combination of HuR and the 3′UTR region of Tp53 mRNA in RTECs. The overexpression of HuR abrogated the inhibitory effect of pcDNA-9935 on the LPS-induced apoptosis of NRK-52E and rat primary RTECs. In conclusion, 9935 exerts its role in septic AKI by suppressing the p53-mediated apoptosis of RTECs, and this essential role of 9935 relies on its destructive effect on HuR-mediated Tp53 mRNA stability.

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

Experimental and Therapeutic Medicine ◽

10.3892/etm.2018.5890 ◽

2018 ◽

Cited By ~ 6

Author(s):

Guang‑Dao Chen ◽

Jun‑Liang Zhang ◽

Yi‑Ting Chen ◽

Ju‑Xing Zhang ◽

Tao Wang ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Superoxide Dismutase ◽

Uncoupling Protein ◽

Kidney Injury ◽

Uncoupling Protein 2 ◽

Mitochondrial Oxidative Stress ◽

Septic Acute Kidney Injury ◽

Superoxide Dismutase 2

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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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