Stretch-induced activation of AMP kinase in the lung requires dystroglycan.
Lung cells are exposed to cyclic stretch during normal respiration and during positive pressure mechanical ventilation administered to support gas exchange. Dystroglycan is a ubiquitously expressed matrix receptor that is required for normal basement membrane formation during embryogenesis and for maintaining the function of skeletal muscle myocytes and neurons where it links cells to matrix. We previously reported that equibiaxial stretch of primary alveolar epithelial cells activated the MAP kinase pathway ERK1/2 through a mechanism that required an interaction between dystroglycan and matrix. We determined whether this mechanism of mechanotransduction activates other signaling cascades in lung epithelium. Exposure of rat epithelial alveolar type II cells (AEC) to cyclic mechanical stretch resulted in activation of 5' AMP-activated protein kinase (AMPK). This response was not affected by pretreatment of AEC with the ERK inhibitor PD98059 but was inhibited by knockdown in dystroglycan expression. Moreover, production of reactive oxygen species was enhanced in mechanically stimulated AEC in which dystroglycan was knocked down. This enhancement was reversed by treatment of AEC with an AMPK activator. Activation of AMPK was also observed in lung homogenates from mice after 15 minutes of noninjurious mechanical ventilation. Furthermore, knockdown of dystroglycan in the lungs of mice using an adenovirus encoding a dystroglycan shRNA prevented the stretch-induced activation of AMPK. These results suggest that exposure to cyclic stretch activates the metabolic sensing pathway AMPK in the lung epithelium and supports a novel role for dystroglycan in this mechanotransduction.
Division of Pulmonary and Critical Care Medicine, The Feinberg School of Medicine, Northwestern University, Chicago, Illinois 60611, USA. s-buding@northwestern.edu
G R Scott
GR
Budinger
Daniela
D
Urich
Phillip J
PJ
DeBiase
Sergio E
SE
Chiarella
Zachary O
ZO
Burgess
Christina M
CM
Baker
Saul
S
Soberanes
Gökhan M
GM
Mutlu
Jonathan C R
JC
Jones
D055372:AMP-Activated Protein Kinases / Q000378:metabolism*; D000256:Adenoviridae; D000818:Animals; D049030:Dystroglycans / Q000378:metabolism*; D004789:Enzyme Activation; D004847:Epithelial Cells / Q000166:cytology / Q000201:enzymology; D008168:Lung / Q000166:cytology / Q000201:enzymology*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D019950:Mitogen-Activated Protein Kinase 1 / Q000378:metabolism; D048052:Mitogen-Activated Protein Kinase 3 / Q000378:metabolism; D011650:Pulmonary Alveoli / Q000166:cytology / Q000201:enzymology; D034741:RNA, Small Interfering / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism; D012121:Respiration, Artificial; D013314:Stress, Mechanical
D034741:RNA, Small Interfering; D017382:Reactive Oxygen Species; D049030:Dystroglycans; D019950:Mitogen-Activated Protein Kinase 1; D048052:Mitogen-Activated Protein Kinase 3; D055372:AMP-Activated Protein Kinases