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

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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The Indirect Implication of SARS-CoV-2 Resulting in Kayexalate Toxicity in a Patient with Acute Kidney Injury

Journal of Renal and Hepatic Disorders ◽

10.15586/jrenhep.v5i1.88 ◽

2021 ◽

Vol 5 (1) ◽

pp. 6-13

Author(s):

Charles E. Middleton IV ◽

William Daley ◽

Neha Varshney

Keyword(s):

Acute Kidney Injury ◽

Virus Disease ◽

Severe Disease ◽

Kidney Injury ◽

Multiple Organ ◽

Subsequent Treatment ◽

Gastrointestinal Complications ◽

Treatment Regimens ◽

Organ Systems ◽

Life Threatening

The clinical features of corona virus disease 2019 (COVID-19) are variable, but the majority of patients experience mild flu-like symptoms. The cases of severe disease include complications such as progressive pneumonia, acute kidney injury, multi-organ failure, and even death. This paper explores the association between COVID-19 and its effect on multiple organ systems and how the subsequent treatment of this disease can itself lead to morbidity and mortality. We present a case which emphasizes the life threatening gastrointestinal complications associated with treatment of acute kidney injury (AKI) in a patient with COVID-19. We conclude that the patients whose treatment regimens utilize medical resins should be closely monitored for gastrointestinal complications so as to mitigate the known adverse effects associated with these drugs, such as colonic mucosal ulceration, perforation, or even death.

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

10.21203/rs.3.rs-935326/v1 ◽

2021 ◽

Author(s):

Weifeng Li ◽

Qiuxia Huang ◽

Jinjin Yu ◽

Jiabao Yu ◽

Yajie Yang ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Kidney Tissue ◽

Kidney Injury ◽

Immunohistochemical Analysis ◽

Inflammatory Factors ◽

Raw264.7 Macrophages ◽

Bioactive Component

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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Ulinastatin improves renal microcirculation by protecting endothelial cells and inhibiting autophagy in a septic rat model

Kidney & Blood Pressure Research ◽

10.1159/000521648 ◽

2022 ◽

Author(s):

Tian Li ◽

Xiaojun Ji ◽

Jingfeng Liu ◽

Xinjie Guo ◽

Ran Pang ◽

...

Keyword(s):

Inflammatory Response ◽

Rat Model ◽

Cecal Ligation ◽

Kidney Tissue ◽

Kidney Injury ◽

Inflammatory Factors ◽

Enzyme Linked Immunosorbent Assay ◽

Sprague Dawley ◽

Male Adult ◽

Renal Microcirculation

Introduction: Increased permeability of the renal capillaries is a common consequence of sepsis-associated acute kidney injury. Vascular endothelial (VE)-cadherin is a strictly endothelial-specific adhesion molecule that can control the permeability of the blood vessel wall. Additionally, autophagy plays an important role in maintaining cell stability. Ulinastatin, a urinary trypsin inhibitor, attenuates the systemic inflammatory response and visceral vasopermeability. However, it is uncertain whether ulinastatin can improve renal microcirculation by acting on the endothelial adhesion junction. Methods: We observed the effect of ulinastatin in a septic rat model using contrast-enhanced ultrasonography (CEUS) to evaluate the perfusion of the renal cortex and medulla. Male adult Sprague-Dawley rats were subjected to cecal ligation and puncture and divided into the sham, sepsis, and ulinastatin groups. Ulinastatin (50,000 U/kg) was injected into the tail vein immediately after the operation. The CEUS was performed to evaluate the renal microcirculation perfusion at 3, 6, 12, and 24 hours after the operation. Histological staining was used to evaluate kidney injury scores. Western blot (WB) was used to quantify the expression of VE-cadherin, LC3II, and inflammatory factors [interleukin -1β (IL-1β), interleukin -6 (IL-6), and tumor necrosis factor-α (TNF-α)] in kidney tissue, and enzyme-linked immunosorbent assay (ELISA) detected serum inflammatory factors and kidney function and early kidney injury biomarker levels. Results: Compared with the sham group, ulinastatin reduced the inflammatory response, inhibited autophagy, maintained the expression of VE-cadherin, and meliorated cortical and medullary perfusion. Conclusion: Ulinastatin effectively protects the adhesion junction and helps ameliorate the perfusion of kidney capillaries during sepsis by the inhibition of autophagy and the expression of inflammatory factors.

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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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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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Effect of Thymoquinone on Acute Kidney Injury Induced by Sepsis in BALB/c Mice

BioMed Research International ◽

10.1155/2020/1594726 ◽

2020 ◽

Vol 2020 ◽

pp. 1-7 ◽

Cited By ~ 2

Author(s):

Li-Peng Guo ◽

Si-Xu Liu ◽

Qin Yang ◽

Hong-Yang Liu ◽

Lu-Lu Xu ◽

...

Keyword(s):

Acute Kidney Injury ◽

Caspase 3 ◽

Nigella Sativa ◽

Cecal Ligation ◽

Kidney Tissue ◽

Kidney Injury ◽

Serum Levels ◽

Caspase 8 ◽

Protective Effects ◽

Caspase 1

Acute kidney injury (AKI) is a common complication of sepsis and has also been observed in some patients suffering from the new coronavirus pneumonia COVID-19, which is currently a major global concern. Thymoquinone (TQ) is one of the most active ingredients in Nigella sativa seeds. It has a variety of beneficial properties including anti-inflammatory and antioxidative activities. Here, we investigated the possible protective effects of TQ against kidney damage in septic BALB/c mice. Eight-week-old male BALB/c mice were divided into four groups: control, TQ, cecal ligation and puncture (CLP), and TQ+CLP. CLP was performed after 2 weeks of TQ gavage. After 48 h, we measured the histopathological alterations in the kidney tissue and the serum levels of creatinine (CRE) and blood urea nitrogen (BUN). We also evaluated pyroptosis (NLRP3, caspase-1), apoptosis (caspase-3, caspase-8), proinflammatory (TNF-α, IL-1β, and IL-6)-related protein and gene expression levels. Our results demonstrated that TQ inhibited CLP-induced increased serum CRE and BUN levels. It also significantly inhibited the high levels of NLRP3, caspase-1, caspase-3, caspase-8, TNF-α, IL-1β, and IL-6 induced by CLP. Furthermore, NF-κB protein level was significantly decreased in the TQ+CLP group than in the CLP group. Together, our results indicate that TQ may be a potential therapeutic agent for sepsis-induced AKI.

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N-acetylcysteine prevents pulmonary edema and acute kidney injury in rats with sepsis submitted to mechanical ventilation

AJP Lung Cellular and Molecular Physiology ◽

10.1152/ajplung.00097.2011 ◽

2012 ◽

Vol 302 (7) ◽

pp. L640-L650 ◽

Cited By ~ 48

Author(s):

Renata Campos ◽

Maria Heloísa Massola Shimizu ◽

Rildo Aparecido Volpini ◽

Ana Carolina de Bragança ◽

Lucia Andrade ◽

...

Keyword(s):

Oxidative Stress ◽

Mechanical Ventilation ◽

Acute Kidney Injury ◽

Lung Injury ◽

Pulmonary Function ◽

Respiratory Mechanics ◽

Cecal Ligation ◽

Weight Ratio ◽

Kidney Injury ◽

Α Subunit

Sepsis is a common cause of acute kidney injury (AKI) and acute lung injury. Oxidative stress plays as important role in such injury. The aim of this study was to evaluate the effects that the potent antioxidant N-acetylcysteine (NAC) has on renal and pulmonary function in rats with sepsis. Rats, treated or not with NAC (4.8 g/l in drinking water), underwent cecal ligation and puncture (CLP) 2 days after the initiation of NAC treatment, which was maintained throughout the study. At 24 h post-CLP, renal and pulmonary function were studied in four groups: control, control + NAC, CLP, and CLP + NAC. All animals were submitted to low-tidal-volume mechanical ventilation. We evaluated respiratory mechanics, the sodium cotransporters Na-K-2Cl (NKCC1) and the α-subunit of the epithelial sodium channel (α-ENaC), polymorphonuclear neutrophils, the edema index, oxidative stress (plasma thiobarbituric acid reactive substances and lung tissue 8-isoprostane), and glomerular filtration rate. The CLP rats developed AKI, which was ameliorated in the CLP + NAC rats. Sepsis-induced alterations in respiratory mechanics were also ameliorated by NAC. Edema indexes were lower in the CLP + NAC group, as was the wet-to-dry lung weight ratio. In CLP + NAC rats, α-ENaC expression was upregulated, whereas that of NKCC1 was downregulated, although the difference was not significant. In the CLP + NAC group, oxidative stress was significantly lower and survival rates were significantly higher than in the CLP group. The protective effects of NAC (against kidney and lung injury) are likely attributable to the decrease in oxidative stress, suggesting that NAC can be useful in the treatment of sepsis.

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Caspase-1-Inhibitor AC-YVAD-CMK Inhibits Pyroptosis and Ameliorates Acute Kidney Injury in a Model of Sepsis

BioMed Research International ◽

10.1155/2021/6636621 ◽

2021 ◽

Vol 2021 ◽

pp. 1-9

Author(s):

Mei Yang ◽

Jin-tao Fang ◽

Ni-shang Zhang ◽

Long-jiang Qin ◽

Yang-yang Zhuang ◽

...

Keyword(s):

Acute Kidney Injury ◽

Cecal Ligation ◽

Kidney Tissue ◽

Kidney Injury ◽

Serum Levels ◽

Interleukin 18 ◽

Tissue Samples ◽

Caspase 1 ◽

Tnf Α ◽

Histologic Changes

Objective. To observe the protective effect of AC-YVAD-CMK on sepsis-induced acute kidney injury in mice and to explore its possible mechanisms primarily. Methods. Eighteen male C57BL/6 mice were randomly divided into sham-operated group (Control), cecal ligation and puncture group (CLP), and CLP model treated with AC-YVAD-CMK group (AC-YVAD-CMK) ( n = 6 in each group). Mice were sacrificed at 24 h after operation, and blood and kidney tissue samples were collected for analyses. Histologic changes were determined microscopically following HE staining. The expression of Ly-6B and CD68 was investigated using immunohistochemistry. Serum concentrations of creatinine (sCR) and blood urea nitrogen (BUN) were measured. Serum levels of interleukin-1β (IL-1β), interleukin-18 (IL-18), TNF-α, and interleukin-6 (IL-6) were determined by ELISA. The expressions of Caspas-1, NLRP-1, IL-1β, and IL-18 in renal tissues were investigated using Western blot. Immunofluorescence staining was used to detect the expression of GSDMD protein in renal tissues. Results. AC-YVAD-CMK treatment significantly alleviates sepsis-induced acute kidney injury, with decreased histological injury in renal tissues, suppresses the accumulation of neutrophils and macrophages in renal tissues, and decreased sCR and BUN level ( P < 0.05 ). Attenuation of sepsis-induced acute kidney injury was due to the prohibited production of inflammatory cytokines and decrease expression of Caspas-1, NLRP-1, IL-1β, and IL-18 in renal tissues. In addition, AC-YVAD-CMK treatment significantly reduced the expression of GSDMD in renal tissues compared to those observed in controls ( P < 0.05 ). Conclusions. We demonstrated a marked renoprotective effect of caspase-1-inhibitor AC-YVAD-CMK in a rat model of sepsis by inhibition of pyroptosis.

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USP10 alleviates sepsis-induced acute kidney injury by regulating Sirt6-mediated Nrf2/ARE signaling pathway

Journal of Inflammation ◽

10.1186/s12950-021-00291-7 ◽

2021 ◽

Vol 18 (1) ◽

Author(s):

Fei Gao ◽

Mingjiang Qian ◽

Guoyue Liu ◽

Wanping Ao ◽

Dahua Dai ◽

...

Keyword(s):

Oxidative Stress ◽

Acute Kidney Injury ◽

Epithelial Cell ◽

Western Blot ◽

Cell Apoptosis ◽

Cell Injury ◽

Kidney Injury ◽

Tubular Epithelial Cell ◽

Renal Tubular Epithelial Cell ◽

Renal Tubular

Abstract Background Severe sepsis, a major health problem worldwide, has become one of the leading causes of death in ICU patients. Further study on the pathogenesis and treatment of acute kidney injury (AKI) is of great significance to reduce high mortality rate of sepsis. In this study, the mechanism by which ubiquitin specific peptidase 10 (USP10) reduces sepsis-induced AKI was investigated. Ligation and perforation of cecum (CLP) was employed to establish C57BL/6 mouse models of sepsis. Hematoxylin-eosin (H&E) staining was performed to detect renal injury. The concentrations of serum creatinine (Cr), urea nitrogen (BUN) and cystatin C (Cys C) were determined using a QuantiChrom™ Urea Assay kit. RT-qPCR and western blot were conducted to assess the USP10 expression level. DHE staining was used to detect reactive oxygen species (ROS) levels. H2O2, MDA and SOD levels were assessed using corresponding colorimetric kits. Western blot was used to examine the expression levels of Bcl-2, Bax, cleaved caspase-3, Sirt6, Nrf2 and HO-1. MTT assay was used to determine cell viability, whereas TUNEL staining and flow cytometry were used to assess cell apoptosis. Results In this study, we found that USP10 was decreased in CLP-induced mouse renal tissues. We identified that USP10 alleviated renal dysfunction induced by CLP. Moreover, USP10 was found to reduce oxidative stress, and abated LPS-induced renal tubular epithelial cell injury and apoptosis. Finally, we discovered that USP10 promoted activation of the NRF2/HO-1 pathway through SIRT6 and attenuated LPS-induced renal tubular epithelial cell injury. Conclusions This study found that USP10 activates the NRF2/ARE signaling through SIRT6. USP10 alleviates sepsis-induced renal dysfunction and reduces renal tubular epithelial cell apoptosis and oxidative stress.

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