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The IRE1/JNK signaling pathway regulates inflammation cytokines and production of glomerular extracellular matrix in the acute kidney injury to chronic kidney disease transition

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Abstract

Background

The transition from acute kidney injury (AKI) to chronic kidney disease (CKD) is extremely complex. Incomplete renal tubule repair, inflammation, and endoplasmic reticulum (ER) stress all play major roles. AKI activates ER stress, and the sensor protein inositol-requiring kinase-1 (IRE1) mediates inflammation by promoting the phosphorylation of C-jun NH2-terminal kinase (JNK). The interleukin-6/signal transducer and activator of transcription 3 (IL-6/STAT3) signaling pathway is associated with the secretion of renal extracellular matrix (ECM) and fibrosis. It remains unclear whether these signaling pathways play a role in the AKI–CKD transition.

Methods

In this study, a mouse model of ischemia–reperfusion (I/R) with bilateral renal artery clipping was used. IRE1 or JNK inhibitors were also injected to confirm their roles in the AKI–CKD transition. The renal function of the mice was determined by observing the pathology of the renal tubules and glomeruli through electron microscopy, immunohistochemistry, western blotting and quantitative real-time PCR.

Results

I/R stimulates ER stress and the IRE1/JNK pathway in the renal tubules in a short period of time, leading to continuous inflammation. Long-term I/R injury activates the STAT3 pathway in the glomeruli, activates mesangial cells proliferation, causes secretion of large amounts of glomerular ECM, and promotes glomerular sclerosis. This damage to the renal tubules and glomeruli is significantly reduced in I/R model mice pretreated with IRE1 or JNK inhibitors.

Conclusion

These findings suggested that the IRE1/JNK pathway regulates the inflammatory cytokines caused by AKI and continues to activate the STAT3 pathway and production of ECM in the glomeruli at late stages, suggesting the feasibility of targeted therapy for the AKI–CKD transition.

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Data availability

All data generated or analysed during this study are included in this published article.

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Acknowledgements

We would like to thank Editage (www.editage.cn) for English language editing.

Funding

This work was supported by a grant from the National Natural Science Foundation of China (Grant No. 81600533, U1904134). This study was also supported via Science and Technology Department of Henan Province (Grant No. 212102310189) the Medical Science and Technology Research Project of Henan Province (Grant No. SBGJ2020002070) and Henan Province Middle-aged and Young Health Science and Technology Innovative Talents (Leader) Project (Grant No. YXKC2020014).

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Author notes

  1. Yan Liang and Lingyun Qu have contributed equally to this paper.

Authors and Affiliations

  1. Department of Nephrology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, 450052, People’s Republic of China

    Yan Liang, Lingyun Qu, Zhenjie Liu, Lulu Liang, Yingzi Wang, Songxia Quan, Yulin Wang & Lin Tang

  2. Research Institute of Nephrology, Zhengzhou University, Zhengzhou, 450052, People’s Republic of China

    Yan Liang, Lingyun Qu, Zhenjie Liu, Lulu Liang, Yingzi Wang, Songxia Quan, Yulin Wang & Lin Tang

  3. Key Laboratory of Precision Diagnosis and Treatment for Chronic Kidney Disease in Henan Province, Zhengzhou, 450052, People’s Republic of China

    Yan Liang & Lulu Liang

  4. Core Unit of National Clinical Medical Research Center of Kidney Disease, Zhengzhou, 450052, People’s Republic of China

    Lulu Liang

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  1. Yan Liang
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Contributions

YL and LQ: carried out literature searches, prepared figures, did data interpretation and writing; ZL, LL, and YW: did writing and editing; SQ and YW: conceptualized the paper, prepared figures, did writing and editing. The authors read and approved the final manuscript.

Corresponding author

Correspondence to Lin Tang.

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All experiments were approved by the Ethics Committee for Animal Research of Wuhan Servicebio Technology CO., LTD (Serivcebio Animal Welfare No. 2021136) and carried out accordingly.

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Liang, Y., Qu, L., Liu, Z. et al. The IRE1/JNK signaling pathway regulates inflammation cytokines and production of glomerular extracellular matrix in the acute kidney injury to chronic kidney disease transition. Mol Biol Rep 49, 7709–7718 (2022). https://doi.org/10.1007/s11033-022-07588-7

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  • DOI: https://doi.org/10.1007/s11033-022-07588-7

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