Hypoxia-Inducible Factor 1α Mediated Pulmonary Fibrosis in C57BL/6 Diabetic Mice via Snail/β-Catenin Pathway

Han Xie, Qing-yan Lin, Hong-yu Kuang, Hong-lei Yin

Article ID: 7257
Vol 37, Issue 4, 2023
DOI: https://doi.org/10.23812/j.biol.regul.homeost.agents.20233704.203
Received: 9 May 2023; Accepted: 9 May 2023; Available online: 9 May 2023; Issue release: 9 May 2023

Abstract

Objective: Diabetic patients have increased susceptibility to pulmonary fibrosis, and chronic tissue hypoxia caused by hyperglycemia can lead to the elevation of hypoxia-inducible factor-1α (HIF-1α). HIF-1α, a major transcription factor and core regulator of cell adaptation to hypoxia, is involved in the fibrosis process. However, its role in diabetes-related pulmonary fibrosis remains unclear. The aim of this study was to analyze the functional role of HIF-1α in the development of pulmonary fibrosis in diabetic mice and explore whether HIF-1α may be a therapeutic target for diabetic pulmonary fibrosis. Methods: Forty male C57BL/6 mice were randomized into four groups of ten: Control group;Control+YC-1 (3-(5’-hydroxymethyl-2’-furyl)-1-benzylindazole, HIF-1 inhibitor);DM (diabetes mellitus);And DM+YC-1. A high-fat diet and streptozotocin-induced diabetic mouse model was established. The lung tissue structure of mice in each group was examined using optical and electron microscopes. HIF-1α and α-smooth muscle actin (α-SMA) in lung tissue were checked for using immunohistochemistry and immunofluorescent staining respectively, western blotting and real-time quantitative PCR (polymerase chain reaction) were used to determine HIF-1α, Zinc finger protein (snail) and β-catenin which were the transcription mediators of epithelial-mesenchymal transformation (EMT), and the content of epithelial cells and mesenchymal markers α-SMA, calcium-adhesion protein (N-cadherin), tight junction protein 1 (ZO-1). Results: Lung coefficient (lung weight/body weight) and mitochondrial numbers in type II alveolar epithelial cells were significantly increased in the DM group, compared to the control group. Diabetic mice had with pulmonary fibrosis. In DM group, the level of α-SMA and HIF-1α were significantly increased in lung homogenate, the expression of mesenchymal markers, snail, and β-catenin were significantly increased, and epithelial cell marker expression was significantly decreased. These indicators were significantly reversed after treatment with the HIF-1α inhibitor YC-1, which ultimately and significantly attenuated pulmonary fibrosis. Conclusions: HIF-1α mediates pulmonary fibrosis in type 2 diabetic mice, through the snail/β-catenin pathway. HIF-1α was involved in the process of EMT and could be a target for prevention and treatment of early pulmonary fibrosis in diabetes.


Keywords

hypoxia-inducible factor-1α (HIF-1α);pulmonary fibrosis;diabetes;epithelial-mesenchymal transformation (EMT);hypoxia


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