Caveolin1 Mediates the Midkine-Induced Angiotensin I Converting Enzyme Signaling in Human Lung Epithelial Cells

Introduction: Midkine (MK), a novel cytokine, is upregulated in acute respiratory distress syndrome (ARDS) patients. MK interacts with the cell surface receptor Notch2 to induce epithelial-mesenchymal transition (EMT) through angiotensin I converting enzyme (ACE) in lung epithelial cells. However, it remains unknown how Notch2 modulates ACE expression, since there is lack of direct interaction between these two molecules. Caveolin1 (Cav1) has been shown to regulate ACE expression. We hypothesized that Cav1 interacts with Notch2 to mediate the MK-induced ACE signaling pathway. Methods: Human lung epithelial cells were used for co-immunoprecipitation to examine Notch2 interaction with Cav1. Cells were stimulated with recombinant human midkine (rhMK) and transfected with Cav1 siRNA to determine the role of Cav1 on Notch2, ACE, and EMT. Results: Cav1 bound specifically with Notch2, but not Notch1, Notch3, or Notch4. Cav1 knockdown blocked the rhMK- induced ACE and EMT signaling in lung epithelial cells. Conclusion: Cav1 is required to mediate the MK-Notch2-ACE signaling pathway. Word count: 150M.Sc