NF-κB mediates the survival of corneal myofibroblast induced by angiotensin II

Hong-Wei Pan, Yu-Hong Cui, Jun-Wen Zeng
Investigative Ophthalmology & Visual Science 2014, 55 (7): 4220-8

PURPOSE: To investigate the role of angiotensin II (Ang II) in the regulation of corneal myofibroblast apoptosis and the possible signaling pathway.

METHODS: Rabbit corneal myofibroblasts were cultured in vitro and the cell phenotype was identified by expression of α-smooth muscle actin (α-SMA) and formation of F-actin. The expression of Ang II type I receptor (AT1R) in keratocytes and corneal myofibroblasts were detected by immunofluorescence staining and Western blot. The effect of Ang II on corneal myofibroblast apoptosis induced by serum starvation and TNFα plus cycloheximide (CHX) was examined by TUNEL, Hoechst 33258 staining, and caspase 3/7 activity assay. The effect of Ang II on nuclear factor-κB (NF-κB)-dependent DNA binding activity and transcriptional activity was studied by electrophoresis mobility shift assay (EMSA) and luciferase reporter assay, respectively. Ang II-induced TGFβ1 secretion by corneal myofibroblasts was determined by ELISA.

RESULTS: Ang II type I receptor expression was more abundant in corneal myofibroblasts compared with keratocytes. Ang II reduced corneal myofibroblasts apoptotic response to serum starvation or treatment with TNFα plus CHX. This protective effect was attenuated in the presence of AT1R antagonist losartan or NF-κB-specific inhibitor Bay11-7082. Ang II increased NF-κB-dependent DNA-binding activity and transcriptional activity, and also increased TGFβ1 production by corneal myofibroblasts.

CONCLUSIONS: Ang II induces corneal myofibroblasts resistance to apoptosis via activating NF-κB signaling pathway, and thus should be further investigated as a possible target for therapy of corneal fibrosis.

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