Involvement of epithelial-mesenchymal transition afforded by activation of LOX-1/ TGF-β1/KLF6 signaling pathway in diabetic pulmonary fibrosis.
Diabetic pulmonary fibrosis is a severe disease that increases mortality risk of diabetes. However, the molecular mechanisms leading to pulmonary fibrosis in diabetes are poorly understood. This study investigated the roles of epithelial-mesenchymal transition (EMT) and the associated molecular mechanisms in streptozotocin (STZ)-induced rat pulmonary fibrosis.



The rat model of diabetic pulmonary fibrosis was established by intraperitoneal injection of a single dose of STZ (35 mg/kg). Typical lesions of diabetic pulmonary fibrosis were observed 8 weeks after STZ injection by hematoxylin-eosin (HE) and Masson staining. Human bronchial epithelial cells (HBECs) and A549 cells were treated by high glucose. Gene or protein expression was measured by real-time PCR, Western blot, immunohistochemistry or immunofluorescence. The knockdown of lectin-like oxidized low density lipoprotein receptor-1 (LOX-1) or transforming growth factor-β1 (TGF-β1) was conducted by siRNA.



Activation of EMT was observed in lung tissues of STZ-induced diabetic rats, exhibiting a loss in the epithelial cell marker E-cadherin and an increase in the mesenchymal marker Vimentin. The protein and mRNA levels of LOX-1, TGF-β1 and krüppel-like factor 6 (KLF6) in the lung tissues were increased. Incubation of HBECs and A549 cells with high glucose activated EMT and induced an increase in LOX-1, TGF-β1 and KLF-6 expression. LOX-1 siRNA inhibited high glucose-induced EMT in HBECs and A549 cells, which correlated with the reduction of TGF-β1. TGF-β1 siRNA decreased the expression of LOX-1 and KLF6.



EMT was involved in the pathological process of diabetic pulmonary fibrosis, which was activated by LOX-1/TGF-β1/KLF6 signaling pathway.
Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China.
Xiao-Zhou
XZ
Zou
Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, China.
Zhi-Cheng
ZC
Gong
Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China.
Ting
T
Liu
Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China.
Fang
F
He
Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China.
Tian-Tian
TT
Zhu
Department of Pharmacy, The Second People's Hospital of Hefei, Hefei, Anhui 230011, China.
Dai
D
Li
Department of Pharmacy, The Second Affiliated Hospital of Nanchang University, Nanchang, Jiangxi 33006, China.
Wei-Fang
WF
Zhang
Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, Hunan 410078, China. Electronic address: junlinjiang@csu.edu.cn.
Jun-Lin
JL
Jiang
Department of Pharmacology, Xiangya School of Pharmaceutical Sciences, Central South University, Changsha, Hunan 410078, China; Hunan Provincial Key Laboratory of Cardiovascular Research, Central South University, Changsha, Hunan 410078, China. Electronic address: huchangping@yahoo.com.
Chang-Ping
CP
Hu
D000072283:A549 Cells; D000818:Animals; D015153:Blotting, Western; D015820:Cadherins / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D004195:Disease Models, Animal; D004847:Epithelial Cells / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D006801:Humans; D000075723:Kruppel-Like Factor 6 / Q000235:genetics / Q000378:metabolism; D008168:Lung / Q000378:metabolism / Q000473:pathology*; D011658:Pulmonary Fibrosis / Q000209:etiology*; D051381:Rats; D060888:Real-Time Polymerase Chain Reaction; D051127:Scavenger Receptors, Class E / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology; D013311:Streptozocin; D053773:Transforming Growth Factor beta1 / Q000235:genetics / Q000378:metabolism; D014746:Vimentin / Q000378:metabolism
D015820:Cadherins; D000075723:Kruppel-Like Factor 6; D051127:Scavenger Receptors, Class E; D053773:Transforming Growth Factor beta1; D014746:Vimentin; D013311:Streptozocin
Diabetes; Epithelial-mesenchymal transition; KLF6; LOX-1; Pulmonary fibrosis; TGF-β1