MiR-22-3p inhibits fibrotic cataract through inactivation of HDAC6 and increase of α-tubulin acetylation.

Objectives: Fibrotic cataract, including posterior capsule opacification (PCO) and anterior subcapsular cataract (ASC), renders millions of people visually impaired worldwide. However, the underlying mechanism remains poorly understood. Here, we report a miRNA-based regulatory pathway that controls pathological fibrosis of lens epithelium.

Materials And Methods: Expression of miR-22-3p and histone deacetylase 6 (HDAC6) in normal and PCO patient samples were measured by qPCR. Human lens epithelial explants were treated with TGF-β2 in the presence or absence of miR-22-3p mimics or inhibitor. Cell proliferation was determined by MTS assay, and migration was tested by transwell assay. Expression of HDAC6 and EMT-related molecules were analysed by Western blot, qPCR and immunocytochemical experiments.

Results: We identify miR-22-3p as a downregulated miRNA targeting HDAC6 in LECs during lens fibrosis and TGF-β2 treatment. Mechanistically, gain- and loss-of-function experiments in human LECs and lens epithelial explants reveal that miR-22-3p prevents proliferation, migration and TGF-β2 induced EMT of LECs via targeting HDAC6 and thereby promoting α-tubulin acetylation. Moreover, pharmacological targeting of HDAC6 deacetylase with Tubacin prevents fibrotic opaque formation through increasing α-tubulin acetylation under TGF-β2 stimulated conditions in both human lens epithelial explants and the whole rat lenses.

Conclusions: These findings suggest that miR-22-3p prevents lens fibrotic progression by targeting HDAC6 thereby promoting α-tubulin acetylation. The 'miR-22-HDAC6-α-tubulin (de)acetylation' signalling axis may be therapeutic targets for the treatment of fibrotic cataract.