Toll-like receptor-4 deficiency alleviates chronic intermittent hypoxia-induced renal injury, inflammation, and fibrosis

  • Yan Zhang
  • Xiaoli SuEmail author
  • Fangfang Zou
  • Tengjuan Xu
  • Pinhua Pan
  • Chengping Hu
Sleep Breathing Physiology and Disorders • Original Article



Obstructive sleep apnea (OSA)-associated chronic kidney disease is mainly caused by chronic intermittent hypoxia (CIH) triggered renal damage. This study aims to investigate the role of toll-like receptor-4 (TLR4) in underlying mechanism involved chronic intermittent hypoxia (CIH)-induced renal damage.


C57BL/6J mice with normal TLR4 (TLR4 WT) or deficient TLR4 (TLR4 KO) were divided into four groups and exposed to normal air (NA) and CIH: TLR4 WT + NA, TLR4 KO + NA, TLR4 WT + CIH, and TLR4 KO + CIH. CIH lasted for 8 h/day and 7 days/week for 6 weeks. Renal injury and inflammation were evaluated by histology and ELISA. Renal tubular apoptosis, macrophages, and fibroblasts recruitment were determined by TUNEL assay, immunofluorescence, and western blot.


In response to CIH, TLR4 deficiency alleviated renal histological injury, renal dysfunction, and fibrosis. TLR4 deficiency ameliorated renal dysfunction (serum BUN and creatinine) and tubular endothelial apoptosis determined by immunofluorescence staining of CD31 and TUNEL, and western blot of apoptotic protein (caspase-3, c-caspase-3, and Bax/Bcl-2 ratio). Furthermore, we also found TLR4 deficiency abrogated CIH-induced macrophages (CD68) and fibroblasts (α-SMA) recruitment, further reducing expression of extra-cellular matrix protein (collagen I and collagen IV) and inflammatory cytokines release (IL-6, TNF-α, and MCP-1). Finally, we used immunohistochemistry to demonstrate that TLR4 deficiency attenuated increased expression of MyD88 and NF-kB p65 after CIH treatment.


Our data suggest that TLR4 plays a vital role in CIH-induced renal injury, inflammation and fibrosis, and inhibition of TLR4 probably provides a therapeutic potential for CIH-induced kidney damage.


Obstructive sleep apnea Toll-like receptor 4 Chronic intermittent hypoxia Renal damage 



The present study was supported by grants from the Central South University Innovation Foundation For Postgraduates (2017zzts209). The sponsor had no role in design or conduct of this research.

Compliance with ethical standards

Conflict of interests

The authors declare that they have no conflict of interest.

Ethical approval

The animal protocol was approved by the Animal Care Committee of Xiangya Hospital, Central South University, in accordance with the National Institutes of Health Guide for the Care and Use of Laboratory Animals.


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Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  • Yan Zhang
    • 1
  • Xiaoli Su
    • 1
    Email author
  • Fangfang Zou
    • 1
  • Tengjuan Xu
    • 1
  • Pinhua Pan
    • 1
  • Chengping Hu
    • 1
  1. 1.Department of Respiratory Medicine, Xiangya Hospital, Key Cite of National Clinical Research Center for Respiratory DiseaseCentral South UniversityChangshaPeople’s Republic of China

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