Histone acetyltransferase and Polo-like kinase 3 inhibitors prevent rat galactose-induced cataract
Histone acetyltransferase and Polo-like kinase 3 inhibitors prevent rat galactose-induced cataract
复制标题
DOI：
10.1038/s41598-019-56414-x
复制
发表时间：
2019-12-27
影响因子：
4.6
通讯作者：
Oki, Masaya
中科院分区：
文献类型：
--
作者：
Kanada, Fumito;Takamura, Yoshihiro;Oki, Masaya
糖尿病性白内障可在幼年时发生，导致视力障碍或失明。糖尿病性白内障形成的详细分子机制仍不完全清楚，并且没有充分记录的预防剂。喂食半乳糖的大鼠和用半乳糖对晶状体进行离体处理被用作糖尿病性白内障的模型。为了评估组蛋白乙酰转移酶的作用，我们使用已知的组蛋白乙酰转移酶 (HAT) 抑制剂进行了白内障预防筛查。在高半乳糖条件下，用 HAT 抑制剂进行离体处理可强烈抑制晶状体浑浊的形成，而添加组蛋白脱乙酰酶 (HDAC) 抑制剂则会加剧浑浊。我们进行了微阵列来鉴定受 HAT 和 HDAC 差异调节的基因，从而发现了一种新的白内障致病因子 Plk3。 Plk3 mRNA 水平与浑浊程度相关，Plk3 抑制可减轻半乳糖诱导的白内障形成。这些发现表明表观遗传控制的 Plk3 影响白内障的形成。我们的结果证明了一种使用 HAT 和 Plk3 抑制剂预防糖尿病性白内障的新方法。
Diabetic cataracts can occur at an early age, causing visual impairment or blindness. The detailed molecular mechanisms of diabetic cataract formation remain incompletely understood, and there is no well-documented prophylactic agent. Galactose-fed rats and ex vivo treatment of lenses with galactose are used as models of diabetic cataract. To assess the role of histone acetyltransferases, we conducted cataract prevention screening with known histone acetyltransferase (HAT) inhibitors. Ex vivo treatment with a HAT inhibitor strongly inhibited the formation of lens turbidity in high-galactose conditions, while addition of a histone deacetylase (HDAC) inhibitor aggravated turbidity. We conducted a microarray to identify genes differentially regulated by HATs and HDACs, leading to discovery of a novel cataract causative factor, Plk3. Plk3 mRNA levels correlated with the degree of turbidity, and Plk3 inhibition alleviated galactose-induced cataract formation. These findings indicate that epigenetically controlled Plk3 influences cataract formation. Our results demonstrate a novel approach for prevention of diabetic cataract using HAT and Plk3 inhibitors.