Involvement of RhoA/ROCK1 signaling pathway in hyperglycemia-induced microvascular endothelial dysfunction in diabetic retinopathy.
Diabetic retinopathy (DR) is a well-known serious complication of diabetes mellitus (DM), and can eventually advance to end-stage blindness. In the early stage of DR, endothelial cell barrier disorganized primarily and tight junction (TJ) protein composition transformed subsequently. The small GTPase RhoA and its downstream effector Rho-associated coiled-coil containing protein kinase 1 (ROCK1) regulate a mass of cellular processes, including cell adherence, proliferation, permeability and apoptosis. Although RhoA inhibitors have provided substantial clinical benefit as hypertonicity therapeutics, their use is limited by complex microenvironment as DR. While ample evidence indicates that TJ can be influenced by the RhoA/ROCK1 signaling, the underlying mechanisms remain incompletely understood. Here, we have uncovered a significant signaling network involved in diabetic retinal microvascular endothelial dysfunction (RMVED). Our results indicated that the activation of RhoA/ROCK1 pathway due to high glucose played a key role in microvascular endothelial cell dysfunction (MVED) by way of directly inducing TJ proteins over-expression during DR. We demonstrated that inhibition of RhoA/ROCK1 may attenuate the hypertonicity of endothelial cell caused by high glucose microenvironment meanwhile. Besides, chemical and pharmacological inhibitors of RhoA/ROCK1 pathway may partly block inflammation due to DR. Simultaneously, the apoptosis aroused by high glucose was also prevented considerably by fasudil, a kind of pharmacological inhibitor of RhoA/ROCK1 pathway. These findings indicate that RhoA/ROCK1 signaling directly modulates MVED, suggesting a novel therapeutic target for DR.
Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University Shanghai 200080, China.
Qian-Yi
QY
Lu
Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University Shanghai 200080, China.
Wei
W
Chen
Department of Ophthalmology, Bengbu Medical College Bengbu 233030, China.
Li
L
Lu
Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University Shanghai 200080, China.
Zhi
Z
Zheng
Department of Ophthalmology, Shanghai First People's Hospital, School of Medicine, Shanghai Jiaotong University Shanghai 200080, China.
Xun
X
Xu
D000818:Animals; D017209:Apoptosis; D002199:Capillary Permeability; D002460:Cell Line; D060833:Cellular Microenvironment; D003930:Diabetic Retinopathy / Q000201:enzymology / Q000209:etiology* / Q000473:pathology / Q000503:physiopathology; D017097:Electric Impedance; D042783:Endothelial Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology; D005947:Glucose / Q000378:metabolism*; D006943:Hyperglycemia / Q000150:complications* / Q000201:enzymology; D008253:Macaca mulatta; D055806:Microvessels / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D047428:Protein Kinase Inhibitors / Q000494:pharmacology; D034622:RNA Interference; D012171:Retinal Vessels / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology / Q000503:physiopathology; D015398:Signal Transduction / Q000187:drug effects; D019108:Tight Junctions / Q000201:enzymology; D014162:Transfection; D054460:rho-Associated Kinases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D020742:rhoA GTP-Binding Protein / Q000378:metabolism*
D047428:Protein Kinase Inhibitors; D054460:rho-Associated Kinases; D020742:rhoA GTP-Binding Protein; D005947:Glucose
ROCK1; RhoA; apoptosis; diabetic retinopathy; endothelial dysfunction; fasudil; tight junction