High glucose induces HSP47 expression and promotes the secretion of inflammatory factors through the IRE1α/XBP1/HIF‑1α pathway in retinal Müller cells

Sun,Xincheng; Chen,Chen; Liu,Hu; Tang,Shaowen

doi:10.3892/etm.2021.10847

High glucose induces HSP47 expression and promotes the secretion of inflammatory factors through the IRE1α/XBP1/HIF‑1α pathway in retinal Müller cells

Authors:
- Xincheng Sun
- Chen Chen
- Hu Liu
- Shaowen Tang
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Affiliations: Department of Ophthalmology, The First Affiliated Hospital of Nanjing Medical University, Nanjing, Jiangsu 210029, P.R. China, Department of Ophthalmology, The Affiliated Changzhou No.2 People's Hospital of Nanjing Medical University, Changzhou, Jiangsu 213003, P.R. China, Department of Epidemiology, School of Public Health, Nanjing Medical University, Nanjing, Jiangsu 211166, P.R. China
Published online on: October 7, 2021 https://doi.org/10.3892/etm.2021.10847
Article Number: 1411

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Abstract

Diabetic retinopathy, a common complication of diabetes, is the leading cause of blindness globally. Müller cells are key players in diabetes‑associated retinal inflammation and dysfunction. However, the pathological changes of Müller cells in response to high glucose (HG) and the underlying mechanism remain unclear. The aim of the present study was to investigate the key role of heat shock protein 47 (HSP47) in HG‑induced unfolded protein and inflammatory responses. Primary mouse Müller cells were starved in serum‑free DMEM overnight and then treated with HG (30 mM) for 0, 6, 12 or 24 h. It was observed that HG (30 mM) significantly induced the protein expression of HSP47, inositol‑requiring transmembrane kinase and endonuclease‑1α (IRE1α) and spliced X‑box‑binding protein 1 (XBP1s) in primary mouse Müller cells compared with the untreated group. In addition, the immunoprecipitation results revealed that HSP47 directly interacted with IRE1α, and this interaction was significantly enhanced by HG exposure for 12 or 24 h compared with the untreated group. Furthermore, small interfering RNA‑mediated silencing of HSP47 significantly suppressed HG‑induced activation of the IRE1α/XBP1s/hypoxia inducible factor‑1 subunit α (HIF‑1α) pathway and upregulation of the mRNA expression levels of the inflammatory cytokines vascular endothelial growth factor, platelet‑derived growth factor subunit B, inducible nitric oxide synthase and angiopoietin‑2 in Müller cells. Furthermore, overexpression of IRE1α or HIF‑1α partially attenuated HSP47‑siRNA‑mediated inhibition of inflammatory cytokine expression in Müller cells. Collectively, these results indicated that HG may induce HSP47 expression and promote the inflammatory response through enhancing the interaction between HSP47 and IRE1α, and activating the IRE1α/XBP1s/HIF‑1α pathway in retinal Müller cells.

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