YAP/TAZ Promote Fibrotic Activity in Human Trabecular Meshwork Cells by Sensing Cytoskeleton Structure Alternation

Abstract

Trabecular meshwork (TM) is the main channel of aqueous humor (AH) outflow and the crucial tissue responsible for intraocular pressure (IOP) regulation. The aberrant fibrotic activity of human TM (HTM) cells is thought to be partially responsible for the increased resistance to AH outflow and elevated IOP. This study aimed to identify the TM cell fibrotic activity biomarker and illustrate the mechanisms of fibrotic activity regulation in HTM cells. We used TGFβ2-treated HTM cells and detected the changes in the cytoskeletal structure, the Yes-associated protein (YAP) and its transcriptional co-activator with PDZ-binding domain (TAZ) activation, and the expression levels of the fibrosis-related proteins Collagen I and α-SMA in HTM cells by immunofluorescence staining or western bolt analyses. The expression of YAP was inhibited using siRNA transfection. The results showed that the expression levels of YAP/TAZ and the fibrosis-related proteins Collagen I and α-SMA in HTM cells were elevated under TGF-β2 treatment, which was correlated with the structural change of the cellular F-actin cytoskeleton. Furthermore, the inhibition of YAP decreased the expression of connective tissue growth factor (CTGF), Collagen I, and α-SMA in HTM cells. These findings demonstrate that YAP/TAZ are potential biomarkers in evaluating the TM cell fibrotic activity, and it could sense cytoskeletal structure cues and regulate the fibrotic activity of TM cells.

Episodic Binge-like Ethanol Reduces Skeletal Muscle Strength Associated with Atrophy, Fibrosis, and Inflammation in Young Rats

“…Ccn2/Ctgf is a target gene for TGF-β signaling, one of the main and most studied profibrotic routes in skeletal muscle and other tissues [ 50 , 53 , 101 , 102 , 103 ] and we found increased levels of Tgf-β, mRNA and protein. Nevertheless, CCN2/CTGF can also be induced by other signaling pathways, working independently or simultaneously with TGF-β, which are involved in pathological conditions and might also be present in alcohol muscle damage, such as hypoxia (through HIF-1α) [ 104 , 105 ], lysophosphatidic acid [ 106 , 107 , 108 ], and YAP/TAZ signaling [ 109 , 110 ]. YAP has been found activated in the liver of patients with a history of alcohol abuse, and it is also activated in the livers of chronic/binge alcohol-treated mice, associated with increased CCN2/CTGF [ 98 ], although whether this happens in skeletal muscle remains unknown.…”