ER stress inducing agents that cause induction of TDAG51 and epithelial adhesion disruption result in epithelial to mesenchymal transition via β‐catenin signaling

Epithelial to mesenchymal transition (EMT) is a process through which endoplasmic reticulum (ER) stress may mediate the progression of chronic kidney disease. Thapsigargin (Tg) induced ER stress produced an EMT response in two human renal proximal tubular epithelial cell (hRPTEC) lines, HK‐2 and primary hRPTEC. We hypothesized that changes in cell shape induced by Tg were mediated by TDAG51 upregulation, resulting in an EMT response through β‐catenin signaling. Tg caused shape change as shown by F‐actin cytoskeletal rearrangement. This was accompanied by ER stress induction, TDAG51 upregulation and β‐catenin cytoplasmic and nuclear translocation. Transfection of TDAG51‐GFP plasmid into HK‐2 cells caused shape change and cytoskeletal rearrangement compared to eGFP controls. Scratch assays showed β‐catenin signaling augmented EMT induced by TGFβ1. Cells on the scratch edge showed greater β‐catenin signaling with vehicle and TGFβ1 treatment and also displayed greater EMT marker α‐smooth muscle actin (SMA) expression. However, Tg disrupted the monolayer and caused β‐catenin signaling accompanied by α‐SMA expression both at the scratch edge and in the monolayer. In conclusion, it appears that Tg induces hRPTEC EMT via β‐catenin signaling. TDAG51 induction via Tg treatment may mediate this effect. Supported by CIHR MOP‐67116 and St. Joseph's Healthcare Hamilton.