Gap junctional intercellular communication and endoplasmic reticulum stress regulate chronic cadmium exposure induced apoptosis in HK-2 cells

Toxicol Lett. 2018 May 15:288:35-43. doi: 10.1016/j.toxlet.2018.02.013. Epub 2018 Feb 11.


Cadmium (Cd), a toxic heavy metal, is known to induce renal toxicity by primarily targeting at renal proximal tubule. Endoplasmic reticulum (ER) stress and gap junctional intercellular communication (GJIC) regulate many pathophysiological processes. Yet, how ER stress and GJIC regulate Cd-induced nephrotoxicity remain elusive. In this study, we treated human proximal tubule (HK-2) cells with 1 μM CdCl2 every other day for 12 days and found that Cd significantly increased cell apoptosis at 10 and 12 days. This cytotoxicity correlated with activation of ER stress and apoptotic signaling evidenced by upregulation of inositol-requiring enzyme 1 (IRE1α), splice X-box binding protein-1 (XBP-1s), and apoptosis signal-regulating kinase 1 (ASK1) proteins. Interestingly, the AKT signaling was activated at 2- and 4-day and then inhibited at 10- and 12-day of Cd treatment; by contrast, Cd decreased GJIC levels at 2- and 4-day followed by a significant increase at 10- and 12-day treatment. Activation of AKT by SC79 or inhibition of GJIC by 18α-glycyrrhetinic acid (18α-GA) completely abolished Cd-induced AKT inhibition and IRE1α-ASK1 activation. Importantly, pretreatment with ER stress inhibitor or 18α-GA significantly mitigated Cd-induced apoptosis. These results suggest that GJIC collaborates with AKT signaling and ER stress in regulating prolonged Cd-treatment-induced apoptosis in HK-2 cells.

Keywords: AKT signaling; Cadmium; ER stress; GJIC; HK-2 cells.

MeSH terms

  • Apoptosis / drug effects*
  • Cadmium Chloride / antagonists & inhibitors
  • Cadmium Chloride / toxicity*
  • Cell Communication / drug effects*
  • Cell Line
  • Cell Survival / drug effects
  • Endoplasmic Reticulum Stress / drug effects*
  • Extracellular Space
  • Gap Junctions / drug effects*
  • Gene Expression Regulation / drug effects
  • Humans
  • Kidney Tubules, Proximal / cytology
  • Kidney Tubules, Proximal / drug effects
  • Oncogene Protein v-akt
  • Reactive Oxygen Species / metabolism
  • Signal Transduction / drug effects


  • Reactive Oxygen Species
  • Oncogene Protein v-akt
  • Cadmium Chloride