TY - JOUR
T1 - Protein kinase A activation alleviates cataract formation via increased gap junction intercellular communication
AU - Du, Yu
AU - Tong, Yuxin
AU - Quan, Yumeng
AU - Wang, Guangyan
AU - Cheng, Hongyun
AU - Gu, Sumin
AU - Jiang, Jean X.
N1 - Funding Information:
The authors thank Dr. Thomas White at Stony Brook University for generously providing Cx46 and Cx50 KO mice, Dr. Francisca M. Acosta for critical reading of the manuscript, and Dr. Songqing Lu for help with statistical analysis and Dr. Rui Hua for technical assistance. The study was supported by the National Institutes of Health RO1 EY012085 and Welch Foundation grant AQ-1507 to J.X.J. Conceptualization, J.X.J.; Methodology, Y.D. and S.G.; Formal Analysis, Y.D. and Y.Q.; Investigation, Y.D. Y.T. and G.W.; Resources, H.C.; Writing-Original Draft, Y.D. and J.X.J.; Writing-Review and Editing, Y.D. J.X.J. and S.G.; Funding Acquisition, J.X.J.; Supervision, J.X.J. The authors declare no competing interests.
Funding Information:
The authors thank Dr. Thomas White at Stony Brook University for generously providing Cx46 and Cx50 KO mice, Dr. Francisca M. Acosta for critical reading of the manuscript, and Dr. Songqing Lu for help with statistical analysis and Dr. Rui Hua for technical assistance. The study was supported by the National Institutes of Health RO1 EY012085 and Welch Foundation grant AQ-1507 to J.X.J.
Publisher Copyright:
© 2023 The Author(s)
PY - 2023/3/17
Y1 - 2023/3/17
N2 - 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.
AB - 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.
KW - Molecular biology
KW - Molecular physiology
KW - Physiology
UR - http://www.scopus.com/inward/record.url?scp=85148006304&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85148006304&partnerID=8YFLogxK
U2 - 10.1016/j.isci.2023.106114
DO - 10.1016/j.isci.2023.106114
M3 - Article
C2 - 36852280
AN - SCOPUS:85148006304
SN - 2589-0042
VL - 26
JO - iScience
JF - iScience
IS - 3
M1 - 106114
ER -