Ulinastatin ameliorates acute kidney injury induced by crush syndrome inflammation by modulating Th17/Treg cells

Yang, Xinyue; Song, Jia; Hou, Shike; Fan, Haojun; Lv, Qi; Liu, Zi-Quan; Ding, Hui; Zhang, Yongzhong; Liu, Jinyang; Dong, Wenlong; Wang, Xue

doi:10.1016/j.intimp.2020.106265

Cited by 36 publications

(30 citation statements)

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“…Our previous studies showed that ulinastatin can protect against severe bowel, lung, heart and other organ damage ( 21 , 22 ). Recent studies have shown that ulinastatin alleviates AKI caused by inflammation in crush syndrome by regulating Th17/Treg cells ( 23 ). As a result, treatments targeting inflammation and blood coagulation may be clinically significant in studies on kidney injury caused by EHS in the future.…”

Section: Discussionmentioning

confidence: 99%

Clinical Characteristics and Risk Factors Associated With Acute Kidney Injury Inpatient With Exertional Heatstroke: An Over 10-Year Intensive Care Survey

Wang

Liu³

et al. 2021

Front. Med.

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Background: Exertional heat stroke (EHS) is a life-threatening injury that can lead to acute kidney injury (AKI). The clinical characteristics of and risk factors for EHS complicated with AKI have been poorly documented.Methods: A retrospective study with EHS admitted to the intensive care unit (ICU) from January 2008 to June 2019 was performed. Data including baseline clinical information at admission, main organ dysfunction, 90-day mortality and total cost of hospitalization were collected.Results: A total of 187 patients were finally included, of which 82 (43.9%) had AKI. AKI patients had more severe organ injury and higher total hospitalization costs than non-AKI patients. Multivariate logistic analysis showed that lymphocyte, neutrophil, D-dimer and myoglobin (MB) ≥ 1,000 ng/ml were independent risk factors for AKI caused by EHS. In addition, SOFA score [hazard ratio (HR) 4.1, 95% confidence interval (95% CI) 1.6–10.8, P = 0.004] and GCS score (HR 3.2, 95% CI 1.2–8.4 P = 0.017) were the risk factor for 90-day mortality in patients with EHS complicated with AKI, with an area under the curve (AUC) of 0.920 (95% CI 0.842–0.998, P < 0.001) and 0.851 (95% CI 0.739–0.962, P < 0.001), respectively. Survival analysis showed that the 90-day mortality in AKI patients was significantly high (P < 0.0001) and the mortality rate of patients with AKI stage 2 was the highest than other stages.Conclusions: EHS complicated with AKI is associated with higher hospitalization costs and poorly clinical outcomes. MB ≥1,000 ng/ml, Inflammation, coagulation were associated with the occurrence and development of AKI. Early treatment strategies based reducing the SOFA and GCS score may be pivotal for improving the prognosis of EHS.

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Section: Discussionmentioning

confidence: 99%

Clinical Characteristics and Risk Factors Associated With Acute Kidney Injury Inpatient With Exertional Heatstroke: An Over 10-Year Intensive Care Survey

Wang

Liu³

et al. 2021

Front. Med.

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“…A total of 24 male Sprague-Dawley rats weighing 180–200 g were maintained under standard laboratory conditions (constant temperature of 25 °C and humidity at 50–60% with a 12 h light and 12 h dark cycle) and had free access to food and water. The CS-AKI model was prepared using a crush injury platform [ 18 , 19 ]. The rats were randomly divided into two groups, including the sham group and the CS group ( n = 12).…”

Section: Methodsmentioning

confidence: 99%

RIG-I, a novel DAMPs sensor for myoglobin, activates NF-κB/caspase-3 signaling in CS-AKI model

Wang

et al. 2021

Military Med Res

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Background Acute kidney injury (AKI) is the main life-threatening complication of crush syndrome (CS), and myoglobin is accepted as the main pathogenic factor. The pattern recognition receptor retinoicacid-inducible gene I (RIG-I) has been reported to exert anti-viral effects function in the innate immune response. However, it is not clear whether RIG-I plays a role in CS-AKI. The present research was carried out to explore the role of RIG-I in CS-AKI. Methods Sprague-Dawley rats were randomly divided into two groups: the sham and CS groups (n = 12). After administration of anesthesia, the double hind limbs of rats in the CS group were put under a pressure of 3 kg for 16 h to mimic crush conditions. The rats in both groups were denied access to food and water. Rats were sacrificed at 12 h or 36 h after pressure was relieved. The successful establishment of the CS-AKI model was confirmed by serum biochemical analysis and renal histological examination. In addition, RNA sequencing was performed on rat kidney tissue to identify molecular pathways involved in CS-AKI. Furthermore, NRK-52E cells were treated with 200 μmol/L ferrous myoglobin to mimic CS-AKI at the cellular level. The cells and cell supernatant samples were collected at 6 h or 24 h. Small interfering RNAs (siRNA) was used to knock down RIG-I expression. The relative expression levels of molecules involved in the RIG-I pathway in rat kidney or cells samples were measured by quantitative Real-time PCR (qPCR), Western blotting analysis, and immunohistochemistry (IHC) staining. Tumor necrosis factor-α (TNF-α) was detected by ELISA. Co-Immunoprecipitation (Co-IP) assays were used to detect the interaction between RIG-I and myoglobin. Results RNA sequencing of CS-AKI rat kidney tissue revealed that the different expression of RIG-I signaling pathway. qPCR, Western blotting, and IHC assays showed that RIG-I, nuclear factor kappa-B (NF-κB) P65, p-P65, and the apoptotic marker caspase-3 and cleaved caspase-3 were up-regulated in the CS group (P < 0.05). However, the levels of interferon regulatory factor 3 (IRF3), p-IRF3 and the antiviral factor interferon-beta (IFN-β) showed no significant changes between the sham and CS groups. Co-IP assays showed the interaction between RIG-I and myoglobin in the kidneys of the CS group. Depletion of RIG-I could alleviate the myoglobin induced expression of apoptosis-associated molecules via the NF-κB/caspase-3 axis. Conclusion RIG-I is a novel damage-associated molecular patterns (DAMPs) sensor for myoglobin and participates in the NF-κB/caspase-3 signaling pathway in CS-AKI. In the development of CS-AKI, specific intervention in the RIG-I pathway might be a potential therapeutic strategy for CS-AKI.

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“…In addition, some studies indicated that Treg also possessed the ability to inhibit Th17-mediated kidney injury (12,45,57,58). Particularly, recent studies reported a specialized Treg type 17 that colocalized with Th17 and exclusively inhibited Th17mediated effect via spatial interaction, IL-10 production, and CCR6 expression (19,59).…”

Section: The Attenuation Of Th17 Effectmentioning

confidence: 99%

Mesenchymal Stem Cell Protects Injured Renal Tubular Epithelial Cells by Regulating mTOR-Mediated Th17/Treg Axis

Luo

Guo

Zhang³

et al. 2021

Front. Immunol.

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The increase in T helper 17 cell (Th17)-mediated pro-inflammatory response and decrease in regulatory T cell (Treg)-mediated anti-inflammatory effect aggravate renal tubular epithelial cell (RTEC) injury. However, increasing evidence indicated that mesenchymal stem cell (MSC) possessed the ability to control the imbalance between Th17 and Treg. Given that Th17 and Treg are derived from a common CD4+ T cell precursor, we summarize the current knowledge of MSC-mediated inhibition of the mammalian target of rapamycin (mTOR), which is a master regulator of CD4+ T cell polarization. During CD4+ T cell differentiation, mTOR signaling mediates Th17 and Treg differentiation via hypoxia-inducible factor-1α (HIF-1α)-dependent metabolic regulation and signaling pathway, as well as mTOR-mediated phosphorylation of signal transducer and activator of transcription (STAT) 3 and 5. Through interfering with mTOR signaling, MSC restrains CD4+ T cell differentiation into Th17, but in turn promotes Treg generation. Thus, this review indicates that MSC-mediated Th17-to-Treg polarization is expected to act as new immunotherapy for kidney injury.

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Ulinastatin ameliorates acute kidney injury induced by crush syndrome inflammation by modulating Th17/Treg cells

Cited by 36 publications

References 36 publications

Clinical Characteristics and Risk Factors Associated With Acute Kidney Injury Inpatient With Exertional Heatstroke: An Over 10-Year Intensive Care Survey

Clinical Characteristics and Risk Factors Associated With Acute Kidney Injury Inpatient With Exertional Heatstroke: An Over 10-Year Intensive Care Survey

RIG-I, a novel DAMPs sensor for myoglobin, activates NF-κB/caspase-3 signaling in CS-AKI model

Mesenchymal Stem Cell Protects Injured Renal Tubular Epithelial Cells by Regulating mTOR-Mediated Th17/Treg Axis

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