Du Yu, Tong Yuxin, Quan Yumeng, Wang Guangyan, Cheng Hongyun, Gu Sumin, Jiang Jean X
Department of Ophthalmology, Lanzhou University Second Hospital; Second Clinical School, Lanzhou University, Lanzhou, Gansu, 730000, China.
Department of Biochemistry and Structural Biology, University of Texas Health Science Center, San Antonio, TX 78229-3900, USA.
iScience. 2023 Feb 2;26(3):106114. doi: 10.1016/j.isci.2023.106114. eCollection 2023 Mar 17.
Cataract is the leading cause of blindness worldwide. Here, we reported a potential, effective therapeutic mean for cataract prevention and treatment. Gap junction communication, an important mechanism in maintaining lens transparency, is increased by protein kinase A (PKA). We found that PKA activation reduced cataracts induced by oxidative stress, increased gap junctions/hemichannels in connexin (Cx) 50, Cx46 or Cx50 and Cx46 co-expressing cells, and decreased reactive oxygen species (ROS) levels. However, ROS reduction was shown in wild-type, Cx46 and Cx50 knockout, but not in Cx46/Cx50 double KO lens. In addition, PKA activation protects lens fiber cell death induced by oxidative stress via hemichannel-mediated glutathione transport. Connexin deletion increased lens opacity induced by oxidative stress associated with reduction of anti-oxidative stress gene expression. Together, our results suggest that PKA activation through increased connexin channels in lens fiber cell decreases ROS levels and cell death, leading to alleviated cataracts.
白内障是全球失明的主要原因。在此，我们报道了一种潜在的、有效的白内障防治方法。间隙连接通讯是维持晶状体透明度的重要机制，蛋白激酶A（PKA）可增强该机制。我们发现，PKA激活可减少氧化应激诱导的白内障，增加连接蛋白（Cx）50、Cx46或Cx50与Cx46共表达细胞中的间隙连接/半通道，并降低活性氧（ROS）水平。然而，野生型、Cx46和Cx50基因敲除小鼠晶状体中ROS水平降低，但Cx46/Cx50双基因敲除小鼠晶状体中未出现ROS水平降低。此外，PKA激活通过半通道介导的谷胱甘肽转运保护氧化应激诱导的晶状体纤维细胞死亡。连接蛋白缺失会增加氧化应激诱导的晶状体混浊，同时抗氧化应激基因表达降低。总之，我们的结果表明，通过增加晶状体纤维细胞中的连接蛋白通道激活PKA可降低ROS水平和细胞死亡，从而减轻白内障。
