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The HMGB1‑RAGE/TLR‑TNF‑α signaling pathway may contribute to kidney injury induced by hypoxia

  • Authors:
    • Cheng Zhang
    • Hui Dong
    • Fengwei Chen
    • Yunxia Wang
    • Jing Ma
    • Guangfa Wang
  • View Affiliations / Copyright

    Affiliations: Department of Respiratory and Critical Medicine, Peking University First Hospital, Beijing 100034, P.R. China
    Copyright: © Zhang et al. This is an open access article distributed under the terms of Creative Commons Attribution License.
  • Pages: 17-26
    |
    Published online on: November 6, 2018
       https://doi.org/10.3892/etm.2018.6932
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Abstract

The hypoxia‑reoxygenation process of obstructive sleep apnea (OSA) may cause oxidative stress injury of the kidney, but the molecular mechanisms are not clear. The present study aimed to investigate whether high mobility group box 1 protein (HMGB1) and its subsequent inflammatory pathway served a role in kidney injury. Adult Sprague Dawley rats were used to establish hypoxia models: Continuous hypoxia, intermittent hypoxia and intermittent hypoxia with hypercapnia. Rat kidney tissues and peripheral blood samples were obtained. Histopathological and ultrastructural changes were observed by light and electron microscopy. Immunohistochemical (IHC) staining was used to detect the distribution of HMGB1. Reverse transcription‑quantitative polymerase chain reaction (RT‑qPCR) was used to detect the expression of HMGB1, receptor for advanced glycosylation end products (RAGE), toll‑like receptor 4 (TLR4), nuclear factor kappa‑light‑chain‑enhancer of active B cells (NF‑κB) p65 subunit, tumor necrosis factor‑α (TNF‑α), interleukin (IL)‑6, NAD‑dependent protein deacetylase sirtuin‑1 (SIRT1), peroxisome proliferator‑activated receptor (PPAR) mRNA in renal tissues. An ELISA was used to detect the expression of soluble TLR2, TLR4, PPAR‑γ, TNF‑α, IL‑6 in peripheral blood. Hematoxylin & eosin staining demonstrated that there was no serious injury to the kidneys due to hypoxia, with the exception of a certain degree of renal tubular epithelial cell vacuolation. By contrast, ultrastructural changes by electron microscopy were more significant in the hypoxia groups compared with the control, including foot process fusion in the glomerulus and degeneration of mitochondria in the proximal convoluted tubules. IHC also indicated increased expression of HMGB1 and nuclear translocation in the hypoxia groups. The results of the RT‑qPCR demonstrated that hypoxia stimulation increased the expression of HMGB1, PPAR, RAGE and TNF‑α mRNA, and decreased the expression of SIRT1 mRNA in kidney tissues (P<0.05). The results of the ELISA suggested that hypoxia stimulation increased the expression of soluble TLR4, TNF‑α and IL‑6 in the peripheral blood, and decreased the expression of soluble TLR2 and PPAR‑γ. In summary, hypoxia stimulation may cause early renal injury at the subcellular level and increase the expression and translocation of HMGB1. Hypoxia also upregulated the mRNA expression of the HMGB1‑RAGE‑TNF‑α pathway in kidney tissue and increased the expression of soluble TLR4, TNF‑α and IL‑6 in the peripheral blood. This suggested that the HMGB1‑RAGE/TLR‑TNF‑α pathway may contribute to the molecular mechanisms of early renal injury induced by hypoxia. The pathway may contain potential markers for OSA‑associated early renal injury and drug intervention targets in the future.
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Copy and paste a formatted citation
Spandidos Publications style
Zhang C, Dong H, Chen F, Wang Y, Ma J and Wang G: The HMGB1‑RAGE/TLR‑TNF‑α signaling pathway may contribute to kidney injury induced by hypoxia. Exp Ther Med 17: 17-26, 2019.
APA
Zhang, C., Dong, H., Chen, F., Wang, Y., Ma, J., & Wang, G. (2019). The HMGB1‑RAGE/TLR‑TNF‑α signaling pathway may contribute to kidney injury induced by hypoxia. Experimental and Therapeutic Medicine, 17, 17-26. https://doi.org/10.3892/etm.2018.6932
MLA
Zhang, C., Dong, H., Chen, F., Wang, Y., Ma, J., Wang, G."The HMGB1‑RAGE/TLR‑TNF‑α signaling pathway may contribute to kidney injury induced by hypoxia". Experimental and Therapeutic Medicine 17.1 (2019): 17-26.
Chicago
Zhang, C., Dong, H., Chen, F., Wang, Y., Ma, J., Wang, G."The HMGB1‑RAGE/TLR‑TNF‑α signaling pathway may contribute to kidney injury induced by hypoxia". Experimental and Therapeutic Medicine 17, no. 1 (2019): 17-26. https://doi.org/10.3892/etm.2018.6932
Copy and paste a formatted citation
x
Spandidos Publications style
Zhang C, Dong H, Chen F, Wang Y, Ma J and Wang G: The HMGB1‑RAGE/TLR‑TNF‑α signaling pathway may contribute to kidney injury induced by hypoxia. Exp Ther Med 17: 17-26, 2019.
APA
Zhang, C., Dong, H., Chen, F., Wang, Y., Ma, J., & Wang, G. (2019). The HMGB1‑RAGE/TLR‑TNF‑α signaling pathway may contribute to kidney injury induced by hypoxia. Experimental and Therapeutic Medicine, 17, 17-26. https://doi.org/10.3892/etm.2018.6932
MLA
Zhang, C., Dong, H., Chen, F., Wang, Y., Ma, J., Wang, G."The HMGB1‑RAGE/TLR‑TNF‑α signaling pathway may contribute to kidney injury induced by hypoxia". Experimental and Therapeutic Medicine 17.1 (2019): 17-26.
Chicago
Zhang, C., Dong, H., Chen, F., Wang, Y., Ma, J., Wang, G."The HMGB1‑RAGE/TLR‑TNF‑α signaling pathway may contribute to kidney injury induced by hypoxia". Experimental and Therapeutic Medicine 17, no. 1 (2019): 17-26. https://doi.org/10.3892/etm.2018.6932
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