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

Peng-Tao Wang; Ning Li; Xin-Yue Wang; Jia-Le Chen; Chen-Hao Geng; Zi-Quan Liu; Hao-Jun Fan; Qi Lv; Shi-Ke Hou; Yan-Hua Gong

doi:10.1186/s40779-021-00333-4

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

RESEARCH | Updated：2023-02-28

- RIG-I, a novel DAMPs sensor for myoglobin, activates NF-κB/caspase-3 signaling in CS-AKI model
- Military Medical Research Vol. 9, Issue 1, Pages: 40-52(2022)
- Affiliations：
  
  1.General Hospital of Tianjin Medical University, Tianjin 300052, China
  2.Institute of Disaster Medicine, Tianjin University, Tianjin 300072, China
  3.State Key Laboratory of Medicinal Chemical Biology, Nankai University, Tianjin 300350, China
  4.Tianjin Key Laboratory of Disaster Medicine Technology, Tianjin 300072, China
  5.Wenzhou Safety (Emergency) Institute, Tianjin University, Wenzhou 325000, Zhejiang China
- Author bio：
  
  * houshike@tju.edu.cn;
  gongyanhua@tju.edu.cn
- Funds：
- DOI：10.1186/s40779-021-00333-4
  CLC：
- Published：2022-02
- Accepted：
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Wang et al.: RIG-I, a novel DAMPs sensor for myoglobin, activates NF-κB/caspase-3 signaling in CS-AKI model. Mil Med Res, 2021, 8: 37.
DOI：

Wang et al.: RIG-I, a novel DAMPs sensor for myoglobin, activates NF-κB/caspase-3 signaling in CS-AKI model. Mil Med Res, 2021, 8: 37. DOI： 10.1186/s40779-021-00333-4.

摘要

Abstract

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 (

=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 (

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.

Conclusions:

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.

CS-AKI model

Mil Med Res

2021

8: 37.

关键词

Keywords

references

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