Upregulation of aldose reductase by homocysteine in type II alveolar epithelial cells.
Homocysteine (Hcy) has recently been recognized as an integral component of several disorders. However, the association between hyperhomocysteinemia (HHcy) and pulmonary disease is not well understood. The combination of two-dimensional electrophoresis and tandem mass spectrometry detected and identified proteins that are differentially expressed in human type II alveolar epithelial cells (A549 cells) treated by Hcy. We found that aldose reductase (AR) showed more abundant expression in the cells. Further, Hcy (100-500microM) could induce a time- and dose-dependent upregulation of AR protein levels. Immunohistochemical staining of cross-sections from HHcy mice lungs also revealed increased expression of AR protein. Intracellular levels of reactive oxygen species (ROS) were remarkably elevated in A549 cells treated with Hcy. Pretreatment of A549 cells with catalase and SOD significantly suppressed the Hcy-induced AR expression, which suggests the involvement of ROS in this process. The major signaling pathway mediating the upregulation of AR was demonstrated to be the Ras/Raf/ERK1/2 pathway. In addition, Hcy might reduce surfactant protein B (SP-B) expression in the cells, which could be significantly attenuated by Alrestatin, an AR inhibitor, indicating a damaging role of Hcy-induced AR elevation in the lung. These results show a novel and unanticipated link between HHcy and AR upregulation that may be a risk factor in pulmonary disease of patients with HHcy.
Jiang
He
H
Department of Physiology and Pathophysiology, Key Laboratory of Molecular Cardiovascular Science, Ministry of Education, School of Basic Medical Science, Peking University, Beijing 100083, People's Republic of China.
Wang
Xiao Fei
XF
Fang
Liang
L
Tang
Chaoshu
C
Zhu
Yi
Y
Wang
Xian
X
D000449:Aldehyde Reductase / Q000378:metabolism*; D000539:Alveolar Process / Q000166:cytology*; D045744:Cell Line, Tumor; D004790:Enzyme Induction / Q000187:drug effects*; D004847:Epithelial Cells / Q000187:drug effects* / Q000201:enzymology*; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D006710:Homocysteine / Q000494:pharmacology*; D006801:Humans; D020543:Proteome / Q000378:metabolism; D017382:Reactive Oxygen Species / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D020543:Proteome; D017382:Reactive Oxygen Species; D006710:Homocysteine; D000449:Aldehyde Reductase; D048049:Extracellular Signal-Regulated MAP Kinases