Oxidized low-density lipoprotein enhances Orai3 expression levels to increase proliferation of human lens epithelial cells

Abstract Background Serum lipid levels, especially of oxidized low-density lipoprotein (oxLDL), are related to the development of cataracts, but the mechanisms underlying the role of oxLDL in cataract development in human lens epithelial cells (HLEpiCs) remain unclear. Calcium (Ca2+) overload is also known to be involved in lens turbidity. Store-operated Ca2+ entry (SOCE) is an important pathway mediating Ca2+ influx in lens epithelial cells. The Orai family proteins, which form a type of SOCE channel, localize at the plasma membrane and control Ca2+ influx in response to the depletion of Ca2+ stores in the endoplasmic reticulum. Methods In the present study, we used RNA sequencing, western blot analyses, cell proliferation assays, Ca2+ measurements, and small interfering (si)RNA transfections to investigate the effects of oxLDL on SOCE and proliferation of human lens epithelial cells (HLEpiCs). Results The key findings of our study that suggest this conclusion are that (1) oxLDL enhances the expression levels of Orai3, but not Orai1 or Orai2, in HLEpiCs in vitro; (2) oxLDL significantly increases the proliferation of HLEpiCs in a concentration-dependent manner; (3) oxLDL significantly increases ATP-induced SOCE without affecting Ca2+ release in HLEpiCs; and (4) knockdown of Orai3 significantly reduces cell proliferation and ATP-induced SOCE in HLEpiCs. Conclusions These findings suggest that Ca2+ signaling altered by overexpression of Orai3 may be a mechanism whereby oxLDL increases HLEpiC proliferation to contribute to the development of cataract. Thus, Orai3 may be a target warranting development for the treatment of cataract associated with obesity or hyperlipidemia.