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The role of Toll-like receptor 4 in high-glucose-induced inflammatory and fibrosis markers in human peritoneal mesothelial cells

  • Nephrology - Original Paper
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Abstract

Purpose

High glucose stimulates peritoneal inflammation and extracellular matrix accumulation in human peritoneal mesothelial cells (HPMCs). However, the roles of Toll-like receptor 4 (TLR4) and TLR2 in high-glucose-induced inflammation and fibrosis in peritoneal dialysis (PD) remain unclear. This study aimed to evaluate the effect of high glucose on TLR2 and TLR4 expression in HPMCs and to assess their impact on peritoneal inflammatory and fibrosis markers.

Methods

Using cultured HPMCs, TLRs expression by high-glucose (50 mM) stimulation was assessed by quantitative real-time PCR. The association of reactive oxygen species (ROS) in high-glucose-induced TLR2 and TLR4 expression was measured by 2′,7′-dichlorodihydrofluorescein diacetate staining with or without ROS inhibitor. In addition, the role of TLR2 and TLR4 on high-glucose-induced inflammatory and fibrosis markers including chemoattractant protein-1 (MCP-1), NF-κB, alpha-smooth muscle actin (α-SMA), transforming growth factor-β (TGF-ß), and fibronectin was evaluated after inhibition of TLR2 and TLR4 by small-interfering RNA (siRNA) or anti-TLR4/TLR2 antibodies, respectively.

Results

High glucose induced TLR1, TLR2, and TLR4 mRNAs expressions. High-glucose-induced TLR4 and TLR2 mRNAs were associated partly with the generation of ROS. Inhibition of TLR4 attenuated the high-glucose-induced expression of MCP-1 mRNA and protein, MyD88 mRNA, nuclear NF-κB p65 protein, TGF-β, fibronectin, and α-SMA mRNA and protein. However, inhibition of TLR2 did not change the expression of MCP-1 mRNA and protein.

Conclusions

High glucose induces inflammatory and fibrosis markers in HPMCs partly through the TLR4/MyD88/NF-κB signaling pathway rather than TLR2. Therefore, TLR4 might be a therapeutic target for ameliorating peritoneal inflammation and fibrosis in PD.

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Acknowledgments

This study was supported by grants from the Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (2012R1A1A3007350), the Korean Healthcare Technology R&D Project, Ministry for Health, Welfare and Family Affairs, Republic of Korea (A111345), and a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health and Welfare, Republic of Korea (HI15C0001).

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Authors and Affiliations

  1. Division of Nephrology, Department of Internal Medicine, Kyungpook National University Hospital, Kyungpook National University School of Medicine, 130 Dongduk Ro, Jung-gu, Daegu, 700-721, South Korea

    Soon-Youn Choi, Hye-Myung Ryu, Ji-Young Choi, Jang-Hee Cho, Chan-Duck Kim, Yong-Lim Kim & Sun-Hee Park

  2. BK21 Plus Biomedical Convergence Program, Department of Biomedical Science, Kyungpook National University, Daegu, South Korea

    Soon-Youn Choi & Yong-Lim Kim

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  1. Soon-Youn Choi
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  2. Hye-Myung Ryu
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  3. Ji-Young Choi
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  4. Jang-Hee Cho
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  5. Chan-Duck Kim
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Correspondence to Sun-Hee Park.

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Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

All procedures performed in studies involving human patients were in accordance with the guidelines of the 2008 version of the Declaration of Helsinki and approved by Institutional Review Board of Kyungpook National University Hospital (IRB 2016-02-034-001).

Informed consent

Informed consent was obtained from all individual participants who agreed to collect residual tissue during the elective surgery.

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Choi, SY., Ryu, HM., Choi, JY. et al. The role of Toll-like receptor 4 in high-glucose-induced inflammatory and fibrosis markers in human peritoneal mesothelial cells. Int Urol Nephrol 49, 171–181 (2017). https://doi.org/10.1007/s11255-016-1430-9

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  • DOI: https://doi.org/10.1007/s11255-016-1430-9

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