Histone acetyltransferase inhibition reverses opacity in rat galactose-induced cataract

Abstract

Cataract, a disease that causes opacity of the lens, is the leading cause of blindness worldwide. Cataracts secondary to diabetes are common, even in young patients, so they are of significant clinical importance. Here, we used an ex vivo model of galactose-induced cataracts in the rat lens to investigate the therapeutic effects of histone acetyltransferase (HAT) inhibitors. Among the tested HAT inhibitors, TH1834 was the only one that could reverse most of the opacity once it had formed in the lens. Combination treatment with C646/CPTH2 and CBP30/CPTH2 also had therapeutic effects. In lens cross-sections, vacuoles were present in the tissue of the cortical equatorial region of untreated cataract samples. In treated cataract samples, lens tissue regenerated to fill the vacuoles. To identify the genes regulated by HAT inhibitors, qRT-PCR was performed on treated and untreated cataract samples to determine candidate genes. Expression of Acta1 and Stmn4, both of which are involved in the cytoskeleton, were altered significantly in C646+CPTH2 samples. Expression of Emd, a nuclear membrane protein, and Prtfdc1, which is involved in cancer cell proliferation, were altered significantly in CBP30+CPTH2 samples. Acta1, Acta2, Arrdc3, Hebp2, Hist2h2ab, Pmf1, Ppdpf, Rbm3, RGD1561694, Slc16a6, Slfn13, Tagln, Tgfb1i1, and Tuba1c in TH1834 samples were significantly altered. These genes were primarily related to regulation of cell proliferation, the cytoskeleton, and cell differentiation. Expression levels increased with the onset of cataracts and was suppressed in samples treated with HAT inhibitors.

Glutamate is effective in decreasing opacity formed in galactose-induced cataract model

“…Histone-related genes include Hist1h2ai, H2afx, H3f3b 53 . In our previous study, histone acetyltransferase (HAT) inhibition prevented and treated galactose-induced cataracts, suggesting an effect of histone-related genes on cataracts 31 , 54 . These findings suggest that in the galactose-induced cataract model, oxidative stress induces ER stress, leading to EMT and apoptosis, which, in turn, results in cataracts (Fig.…”

“…These results indicate that glutamate may be effective as a therapeutic agent to reduce lens opacity in diabetic cataracts. We also suggest that further comparisons with agents that have shown therapeutic efficacy in the past in our laboratory may lead to novel approaches to elucidating the pathogenesis of diabetic cataracts 30 , 31 .…”

Ocular surface immune transcriptome and tear cytokines in corneal infection patients

“…This may indicate the important role of this gene in regulating corneal cell differentiation and proliferation. In a previous study conducted on rats, it was found that the expression level of this gene increased with the onset of cataracts in an ex vivo model ( Nagaya et al., 2022 ). Cataracts are an eye condition that causes cloudiness and opaqueness of the lens ( Nagaya et al., 2022 ).…”

“…In a previous study conducted on rats, it was found that the expression level of this gene increased with the onset of cataracts in an ex vivo model ( Nagaya et al., 2022 ). Cataracts are an eye condition that causes cloudiness and opaqueness of the lens ( Nagaya et al., 2022 ). Whereas, in conjunctiva, the study found that the expression of HOPX was significantly reduced, in addition to the ribosomal protein genes.…”

HIF-1 inhibition reverses opacity in a rat model of galactose-induced cataract

“…We have previously reported that histone acetyltransferase (HAT) and ATM inhibitors decrease opacity in the galactose-induced cataract model [ 17 , 56 ]. Among HAT inhibitors, TH1834, which targets TIP60, has exhibited therapeutic effects by decreasing opacity [ 56 ]. Furthermore, ATM is activated by autophosphorylation through acetylation by TIP60 [ 69 ].…”