Background/Aims: Both endothelin-1 (ET-1) and the renin-angiotensin system (RAS) are implicated in the pathogenesis and progression of chronic obstructive pulmonary disease (COPD). In the present study, we explored the interaction between ET-1 and the RAS by examining the effect of ET-1 on angiotensin-converting enzyme-2 (ACE2) expression and activity in human bronchial epithelial cells (HBEpCs). Methods: HBEpCs were treated with ET-1 (1, 10, 20, 40 or 50 nmol/l) for 6, 12, 18, 24 or 30 h with or without the transcription inhibitor actinomycin D, endothelin A (ETA) receptor blocker BQ123, endothelin B receptor blocker BQ788, or different kinase inhibitors. Results: ET-1 decreased the ACE2 mRNA level in a dose- and time-dependent manner within 24 h, which led to dose-dependent downregulation of the ACE2 promoter activity, protein level and the cell membrane ACE2 activity. Actinomycin D (1 mg/ml), BQ123 (1 μmol/l), and the p38 mitogen-activated protein kinase (MAPK) siRNA and inhibitor PD169316 (25 μmol/l) completely abolished the effect of ET-1 on ACE2 expression in HBEpCs. Conclusion: ET-1 downregulates ACE2 expression and activity at the transcription level in HBEpCs via the ETA receptor by a p38 MAPK-dependent mechanism. This is the first evidence of crosstalk between the ET-1/ETA axis and the RAS in regard to the pathogenesis and progression of COPD.

Keywords:
Endothelin-1, Endothelin A receptor, Angiotensin-converting enzyme-2, Chronic obstructive pulmonary disease, Bronchial epithelial cell, p38 mitogen-activated protein kinase
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2013
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