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Involvement of LOX-1in Pulmonary Epithelial-mesenchymal Transition in Diabetic Rats

Author: ZouXiaoZhou
Tutor: HuChangPing
School: Central South University
Course: Pharmacology
Keywords: Diabetic pulmonary fibrosis High glucose Epithelial-mesenchymal transition Lectin-like oxidized low density lipoproteinreceptor-1 Transforming growth factor β-1 Kruppel-like factors6
CLC: R965
Type: Master's thesis
Year: 2013
Downloads: 4
Quote: 0
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Abstract


BACKGROUND:Diabetes mellitus (DM) is a metabolic disease which is characterized by chronic hyperglycemia, leading to metabolic disorder, dysfunction and structure changes of many tissues and organs. This malady may cause a number of diabetic complications, among which diabetic pulmonary fibrosis is one of chronic complications. Emerging evidence suggests that injured epithelial cells via epithelial-mesenchymal transition (EMT) may contribute to pulmonary fibrosis. Transforming growth factor-β1(TGF-β1) is the most critical signaling element in tissue fibrosis, which is related to metabolism of extracellular matrix (ECM) and the formation of tissue fibrosis. It has been shown that TGF-β1may serve as the significant inducer of EMT in the early stage of pulmonary fibrosis. Lectin-like oxidized low density lipoprotein receptor-1(LOX-1), a specific receptor for oxidized low density lipoprotein (ox-LDL), was found on the surface of vascular endothelial cells in1997. LOX-1plays critical roles in multiple signal transduction pathways and is involved in the process of oxidative stress and inflammation. Recent studies have demonstrated that LOX-1mediates collagen deposition and tissue fibrosis induced by TGF-01. Moreover, high glucose can induce the expression of LOX-1, which may up-regulate TGF-β1. Kruppel-like factors6(KLF6) is a zinc finger transcription factor, which regulates growth, differentiation, proliferation and apoptosis of many kinds of cells and plays a significant role in many diseases. KLF6has been found to be involved in the process of EMT in renal tubular epithelial cells induced by TGF-β1. In the present study, we tested whether the expression of LOX-1changed in diabetic pulmonary fibrosis and whether LOX-1mediates EMT through interacting with the singal pathways of KLF6/TGF-β1in diabetic pulmonary fibrosis.METHODS:Rats were divided into two groups which are control and type2diabetic rats. Type2diabetic rats were established by bonus injection of streptozotocin (STZ,35mg/kg, intraperitonealy) and fed high-fat and high-glucose diet. After8weeks the concentration of fasting blood glucose (FBG) was measured. Then these rats were fed with high-fat and high-glucose for another4weeks. The evaluation of pulmonary morphology including pathological changes and collagen deposition were examined by Hematoxylin-eosin or Masson trichrome staining. The protein expression of LOX-1, TGF-β1, KLF6, vimentin and E-cadherin were examined by immunohistochemistry (IHC). The mRNA expression of LOX-1, TGF-β1, KLF6, vimentin and E-cadherin were examined by real-time PCR. The protein expression of E-cadherin was measured by Western blot.RESULT:Compared with the control group, the level of fasting blood glucose was markedly increased in diabetic rats. Diabetic rats revealed severe pulmonary fibrotic injuries as shown by interalveolar septum thickening, mesenchyma infiltration with inflammatory cells and fibroplasias as well as increased collagen deposition. Compared with the control group, the expression of mRNA and protein of LOX-1, TGF-β1and KLF6in the lung tissue was up-regulated in diabetic rats. The expression of mRNA and protein of vimentin, the biomarker of EMT were up-regulated in the lung tissues of diabetic rats. According to IHC, the protein expression of E-cadherin around alveoli was down-regulated obviously in the lung tissues of diabetic rats.CONCLUSION:LOX-1may induce EMT during diabetic pulmonary fibrosis through interacting with the signal pathways of KLF6/TGF-β1.

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