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

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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Polydatin Attenuates Cisplatin-Induced Acute Kidney Injury by Inhibiting Ferroptosis

Oxidative Medicine and Cellular Longevity ◽

10.1155/2022/9947191 ◽

2022 ◽

Vol 2022 ◽

pp. 1-14

Author(s):

Lu Zhou ◽

Peng Yu ◽

Ting-ting Wang ◽

Yi-wei Du ◽

Yang Chen ◽

...

Keyword(s):

Acute Kidney Injury ◽

Kidney Injury ◽

Inhibitory Effect ◽

Ros Generation ◽

Molecular Events ◽

Mda Content ◽

Effect Of Pd ◽

In Cis

Cisplatin is widely used in the treatment of solid tumors, but its application is greatly limited due to its nephrotoxicity; thus, there is still no effective medicine for the treatment of cisplatin-induced acute kidney injury (Cis-AKI). We previously identified that polydatin (PD) exerts nephroprotective effects by antioxidative stress in AKI models. Recent evidence suggests that oxidative stress-induced molecular events overlap with the process of ferroptosis and that there are common molecular targets, such as glutathione (GSH) depletion and lipid peroxidation. Nevertheless, whether the nephroprotective effect of PD is related to anti-ferroptosis remains unclear. In this study, the inhibitory effect of PD on ferroptosis was observed in both cisplatin-treated HK-2 cells (20 μM) in vitro and a Cis-AKI mouse model (20 mg/kg, intraperitoneally) in vivo, characterized by the reversion of excessive intracellular free iron accumulation and reactive oxygen species (ROS) generation, a decrease in malondialdehyde (MDA) content and GSH depletion, and an increase in glutathione peroxidase-4 (GPx4) activity. Remarkably, PD dose-dependently alleviated cell death induced by the system Xc− inhibitor erastin (10 μM), and the effect of the 40 μM dose of PD was more obvious than that of ferrostatin-1 (1 μM) and deferoxamine (DFO, 100 μM), classical ferroptosis inhibitors. Our results provide insight into nephroprotection with PD in Cis-AKI by inhibiting ferroptosis via maintenance of the system Xc−-GSH-GPx4 axis and iron metabolism.

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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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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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Silencing Long Non-coding RNA Kcnq1ot1 Limits Acute Kidney Injury by Promoting miR-204-5p and Blocking the Activation of NLRP3 Inflammasome

Frontiers in Physiology ◽

10.3389/fphys.2021.721524 ◽

2021 ◽

Vol 12 ◽

Author(s):

JunTao Wang ◽

Peng Jiao ◽

XiaoYing Wei ◽

Yun Zhou

Keyword(s):

Cell Proliferation ◽

Acute Kidney Injury ◽

Nlrp3 Inflammasome ◽

Kidney Injury ◽

Human Kidney ◽

Inflammasome Activation ◽

Nlrp3 Inflammasome Activation ◽

Apoptosis And Inflammation

Acute kidney injury (AKI) is a critical clinical disease characterized by an acute decrease in renal function. Long non-coding RNAs (LncRNAs) are important in AKI. This study aimed to explore the mechanism of lncRNA Kcnq1ot1 in AKI by sponging microRNA (miR)-204-5p as a competitive endogenous RNA (ceRNA). AKI mouse model and hypoxia/reoxygenation (H/R) model of human kidney (HK) cells were established. Kcnq1ot1 expression, cell proliferation, and apoptosis were measured. Binding relations among Kcnq1ot1, miR-204-5p, and NLRP3 were verified. Pathological changes and cell apoptosis were detected. The results showed that Kcnq1ot1 was highly expressed in the AKI model in vivo and in vitro. Kcnq1ot1 knockdown promoted cell proliferation and prevented apoptosis and inflammation. Furthermore, Kcnq1ot1 inhibited miR-204-5p expression by competitively binding to miR-204-5p in HK-2 cells. miR-204-5p targeted NLRP3 and NLRP3 overexpression averted the inhibiting effect of miR-204-5p on apoptosis and inflammation in HK-2 cells in vitro. Kcnq1ot1 knockdown in vivo promoted miR-204-5p expression, inhibited NLRP3 inflammasome activation, reduced levels of SCr, BUN, and KIM-1, and thus alleviated AKI and reduced apoptosis. In summary, silencing lncRNA Kcnq1ot1 inhibited AKI by promoting miR-204-5p and inhibiting NLRP3 inflammasome activation.

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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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DDAH-2 alleviates contrast medium iopromide-induced acute kidney injury through nitric oxide synthase

Clinical Science ◽

10.1042/cs20190455 ◽

2019 ◽

Vol 133 (23) ◽

pp. 2361-2378 ◽

Cited By ~ 4

Author(s):

Heng-Huei Lin ◽

Tzong-Shyuan Lee ◽

Shing-Jong Lin ◽

Yi-Chen Yeh ◽

Tse-Min Lu ◽

...

Keyword(s):

Nitric Oxide ◽

Acute Kidney Injury ◽

Nitric Oxide Synthase ◽

Protective Effect ◽

Contrast Medium ◽

Kidney Tissue ◽

Kidney Injury ◽

Ros Generation ◽

Oxide Synthase

Abstract Background: Contrast medium-induced acute kidney injury (CI-AKI) is one of the most common causes of hospital-acquired acute renal failure. However, the pathogenesis of CI-AKI remains unclear. Asymmetric dimethylarginine (ADMA) is an endogenous nitric oxide synthase (NOS) inhibitor that is largely metabolised by dimethylarginine dimethylaminohydroxylase (DDAH) in humans. Two isoforms of DDAH exist, namely, DDAH-1 and DDAH-2. In the present study, we examined whether the DDAH-2/ADMA/NOS pathway is involved in the pathogenesis of CI-AKI. Methods and Results: Exposure to the contrast medium iopromide led to increase in creatinine and blood urea nitrogen (BUN) levels, accumulation of ADMA, increase in reactive oxygen species (ROS) generation, and an inflammatory response in mice kidney tissue. The injection of adenovirus-harbouring DDAH-2 lowered renal ADMA levels and had a reno-protective effect against contrast-medium injury by decreasing cell apoptosis, ROS, and fibrosis. By contrast, contrast medium-induced renal injury was exacerbated in heterozygous DDAH-2 knockout mice. In the in vitro study, overexpression of DDAH-2 increased the levels of nitrite and intracellular cGMP, while the DDAH-2 knockdown induced the opposite effect. These findings were also observed in the in vivo sample. Conclusions: Our findings provide the first evidence that the DDAH-2/ADMA/NOS pathway is involved in the pathogenesis of CI-AKI and that the protective effect of DDAH-2 probably arises from the modulation of NOS activity, oxidative stress, and the inflammatory process.

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Overexpression of TOLLIP Protects against Acute Kidney Injury after Paraquat Intoxication through Inhibiting NLRP3 Inflammasome Activation Modulated by Toll-Like Receptor 2/4 Signaling

Mediators of Inflammation ◽

10.1155/2021/5571272 ◽

2021 ◽

Vol 2021 ◽

pp. 1-14

Author(s):

Qiang Zheng ◽

Hang Zhao ◽

Dong Jia ◽

Xu Han ◽

Zhenning Liu ◽

...

Keyword(s):

Acute Kidney Injury ◽

Nlrp3 Inflammasome ◽

Cell Apoptosis ◽

Kidney Injury ◽

Inflammasome Activation ◽

Toll Like Receptor ◽

Nlrp3 Inflammasome Activation ◽

Toll Like Receptor 2

Paraquat (PQ) can cause multiorgan failure including acute kidney injury (AKI). Our prior study showed that Toll-interacting protein (TOLLIP) protected against PQ-induced acute lung injury. However, the role of TOLLIP in PQ-induced AKI remains undefined. This study was aimed at understanding the role and mechanism of TOLLIP in AKI. Six-eight-week-old male Wistar rats were intraperitoneally injected with 25 mg/kg PQ to induce AKI for 24 h in vivo. HK-2 cells were treated with 300 μM PQ for 24 h to induce cellular injury in vitro or 300 μM PQ and 5 μM nuclear factor-κB (NF-κB) inhibitor BAY11-7082 for 24 h. Rats were infected with adenovirus carrying TOLLIP shRNA via tail vein injection and HK-2 cells with adenovirus carrying TOLLIP shRNA or TOLLIP 48 h before PQ exposure. Results showed that TOLLIP and Toll-like receptor 2/4 (TLR2/4) expressions were boosted in the kidney after PQ intoxication. The toxic effect of PQ on the kidney and HK-2 cells was exacerbated by TOLLIP knockdown, as evidenced by aggravated glomerulus and tubule injury, inflammatory infiltration, and cell apoptosis in the kidney and increased loss of cell viability and apoptotic cells in HK-2 cells. TOLLIP knockdown also enhanced PQ-induced NLR family pyrin domain-containing 3 (NLRP3) inflammasome activation in vivo and in vitro and TLR2/4-NF-κB signaling in vitro, reflected by increased contents of proinflammatory cytokines and expressions of NLRP3 inflammasome-related proteins in the kidney and HK-2 cells and expressions of TLR2, TLR4, and nuclear NF-κB p65 in HK-2 cells. However, TOLLIP overexpression inhibited PQ-induced loss of cell viability, cell apoptosis, NLRP3 inflammasome activation, and TLR2/4-NF-κB signaling in vitro. Additionally, BAY11-7082 abolished TOLLIP knockdown-induced NLRP3 inflammasome activation in vitro, indicating that TOLLIP protected against NLRP3 inflammasome activation in PQ-induced AKI through inhibiting TLR2/4-NF-κB signaling. This study highlights the importance of TOLLIP in AKI after PQ intoxication.

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Cisplatin induces acute kidney injury and pyroptosis in mice through the exosome miR-122/ELAVL1 regulatory axis

10.21203/rs.3.rs-41893/v1 ◽

2020 ◽

Author(s):

Bei Zhu ◽

Xiaoshuang Ye ◽

Fei Gao ◽

Yun Bai ◽

Zhouyi Chan ◽

...

Keyword(s):

Acute Kidney Injury ◽

Kidney Diseases ◽

Kidney Tissue ◽

Kidney Injury ◽

Regulation Mechanism ◽

Substrate Protein ◽

Functional Components ◽

Hk2 Cells

Abstract Background Although cisplatin is an effective chemotherapeutic drug for the treatment of various cancers, its clinical application is limited due to its side effects, especially nephrotoxicity. Unfortunately, Acute kidney injury (AKI) caused by cisplatin remains one of the main obstacles to cancer treatment. Increasing evidence suggests that renal inflammation and pyroptotic inflammatory cell death of tubular epithelial cells (RTECs) mainly determine the progression and outcome of cisplatin-induced AKI. However, it is not clear how cisplatin regulates the pyroptosis of RTECs cells in AKI. The current study aimed to determine the regulation mechanism of AKI induced by cisplatin. In vivo, cisplatin was used to induce AKI. H&E staining of mouse kidney tissue sections and serological indicators of kidney injury (including BUN, serum creatinine and TNF-α) were detected. The important substrate protein GSDMD and key target caspase-1 of pyroptosis were detected by immunohistochemistry and western blot, respectively. In vitro, cisplatin significantly induces HK-2 cells pyroptosis. Furthermore, Cisplatin transmits HK2 cells pyroptosis signals to surrounding cells in the form of exosomes. Previous studies have shown that exosomes are involved in kidney physiology and the pathogenesis of various kidney diseases/disorders. MicroRNAs (miRNAs) are the main functional components of exosomes. Results Further research shows that exosome miR-122 negatively regulates the pyrolysis of HK2 cells. Finally, we elucidated that exosome miR-122 participates in cisplatin induced AKI regulation by regulating ELAVL1 expression. Conclusions In conclusion, these results suggest that exosome miR-122 inhibits pyroptosis and AKI by targeting ELAVL1 under cisplatin treatment, which will provide a potential target for the treatment of AKI.

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Acetylbritannilactone attenuates contrast-induced acute kidney injury through its anti-pyroptosis effects

Bioscience Reports ◽

10.1042/bsr20193253 ◽

2020 ◽

Vol 40 (2) ◽

Cited By ~ 1

Author(s):

Fei Chen ◽

Jingchao Lu ◽

Xiuchun Yang ◽

Bing Xiao ◽

Huiqiang Chen ◽

...

Keyword(s):

Acute Kidney Injury ◽

Renal Damage ◽

Kidney Injury ◽

Underlying Mechanism ◽

Protective Effects ◽

Nucleotide Binding Domain ◽

Caspase 1 ◽

Pro Inflammatory Cytokines

Abstract Contrast-induced acute kidney injury (CI-AKI) is a severe complication caused by intravascular applied radial contrast media (CM). Pyroptosis is a lytic type of cell death inherently associated with inflammation response and the secretion of pro-inflammatory cytokines following caspase-1 activation. The aim of the present study was to investigate the protective effects of acetylbritannilactone (ABL) on iopromide (IOP)-induced acute renal failure and reveal the underlying mechanism. In vivo and in vitro, IOP treatment caused renal damage and elevated the caspase-1 (+) propidium iodide (PI) (+) cell count, interleukin (IL)-1β and IL-18 levels, lactate dehydrogenase (LDH) release, and the relative expression of nucleotide-binding domain, leucine-rich repeat containing protein 3 (NLRP3), apoptosis-associated speck-like protein (ASC), and gasdermin D (GSDMD), suggesting that IOP induces AKI via the activation of pyroptosis. Furthermore, the pretreatment of ABL partly mitigated the CI-AKI, development of pyroptosis, and subsequent kidney inflammation. These data revealed that ABL partially prevents renal dysfunction and reduces pyroptosis in CI-AKI, which may provide a therapeutic target for the treatment of CM-induced AKI.

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SIRT1 attenuates sepsis-induced acute kidney injury via Beclin1 deacetylation-mediated autophagy activation

Cell Death and Disease ◽

10.1038/s41419-021-03508-y ◽

2021 ◽

Vol 12 (2) ◽

Author(s):

Zhiya Deng ◽

Maomao Sun ◽

Jie Wu ◽

Haihong Fang ◽

Shumin Cai ◽

...

Keyword(s):

Acute Kidney Injury ◽

Protective Effect ◽

Cell Model ◽

Kidney Injury ◽

Underlying Mechanism ◽

Autophagy Induction ◽

Promising Therapeutic Approach ◽

Related Proteins ◽

Caecal Ligation And Puncture

AbstractOur previous studies showed that silent mating-type information regulation 2 homologue-1 (SIRT1, a deacetylase) upregulation could attenuate sepsis-induced acute kidney injury (SAKI). Upregulated SIRT1 can deacetylate certain autophagy-related proteins (Beclin1, Atg5, Atg7 and LC3) in vitro. However, it remains unclear whether the beneficial effect of SIRT1 is related to autophagy induction and the underlying mechanism of this effect is also unknown. In the present study, caecal ligation and puncture (CLP)-induced mice, and an LPS-challenged HK-2 cell line were established to mimic a SAKI animal model and a SAKI cell model, respectively. Our results demonstrated that SIRT1 activation promoted autophagy and attenuated SAKI. SIRT1 deacetylated only Beclin1 but not the other autophagy-related proteins in SAKI. SIRT1-induced autophagy and its protective effect against SAKI were mediated by the deacetylation of Beclin1 at K430 and K437. Moreover, two SIRT1 activators, resveratrol and polydatin, attenuated SAKI in CLP-induced septic mice. Our study was the first to demonstrate the important role of SIRT1-induced Beclin1 deacetylation in autophagy and its protective effect against SAKI. These findings suggest that pharmacologic induction of autophagy via SIRT1-mediated Beclin1 deacetylation may be a promising therapeutic approach for future SAKI treatment.

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