Dual Role Of Inositol-Requiring Enzyme 1 Alpha (Ire-1 Alpha) In Cd-Induced Apoptosis In Human Renal Tubular Epithelial Cells: Endoplasmic Reticulum Stress And Stat3 Signaling Activation

Cadmium (Cd) is a nephrotoxicant that primarily damages renal proximal tubular cells. Endoplasmic reticulum (ER) stress is mechanistically linked to Cd-induced renal injury. Inositol-requiring enzyme 1 (IRE-1 alpha) is the most conserved ER stress transducer protein, which has both kinase and endonuclease activities. This study aimed to investigate whether the two enzymatic activities of IRE-1 alpha have different effects in its regulation of Cd-induced apoptosis. Human proximal tubular (HK-2) cells were treated with 20 mu M CdCl2 for 0-24 h, and mice were fed with Cd-containing drinking water (100-400 mg/L) for 24 weeks. We found that Cd increased cell apoptosis in HK-2 cells and mouse kidneys in a time-dependent manner. Such cytotoxicity was correlated with activation of ER stress, evidenced by upregulation of IRE-1 alpha and its target protein spliced X-box binding protein-1 (XBP-1 s). Interestingly, inhibition of IRE-1 alpha kinase activity by KIRA6 was more protective against Cd-induced apoptosis than inhibition of its RNase activity by STF-083010. Mechanistically, Cd promoted the binding of IRE-1 alpha with signal transducer and activator of transcription-3 (STAT3) leading to elevated phosphorylation of STAT3 at Ser727 and thus inactivation of STAT3 signaling, which resulted in aggravation of Cd-induced apoptosis in HK-2 cells. Collectively, our findings indicate that IRE-1 alpha coordinate ER stress and STAT3 signaling in mediating Cd-induced renal toxicity, suggesting that targeting IRE-1 alpha might be a potential therapeutic approach for Cd-induced renal dysfunction and disease.