The small molecule chemical chaperone 4‐Phenylbutyrate inhibits epithelial‐to‐mesenchymal transition in human renal proximal tubular epithelial cells

We have shown that thapsigargin (Tg), an endoplasmic reticulum (ER) stress inducer and activator of the unfolded protein response (UPR), causes epithelial‐to‐mesenchymal transition (EMT), the process by which epithelial cells transform to myofibroblasts. Myofibroblasts contribute to renal fibrosis and the progression of chronic kidney disease through their accumulative production of extracellular matrix. We hypothesize that EMT can be repressed through the use of low molecular weight chemical chaperones, such as 4‐Phenylbutyrate (4‐PBA) and tauroursodeoxycholic acid (TUDCA), in human renal proximal tubular epithelial cells (hRPTECs). 4‐PBA and TUDCA were found to inhibit hRPTEC death from Tg and TGFβ1 treatments as determined by LDH and TUNEL assays. Immunofluorescent labeling of myofibroblast markers showed that both 4‐PBA and TUDCA inhibited F‐actin cytoskeletal rearrangements and repressed β‐Catenin nuclear translocation in TGFβ1‐induced EMT. 4‐PBA inhibited the expression of ER stress marker GRP94 and myofibroblast marker α‐smooth muscle actin. TUDCA inhibited the expression of ER stress marker GRP78 and the focal adhesion complex component vinculin. Both 4‐PBA and TUDCA demonstrated partial inhibitory activity against Tg‐ and TGFβ1‐induced EMT in HK‐2 cells. 4‐PBA was found to inhibit TGFβ1‐induced EMT in primary hRPTECs. Funding was provided by St. Joseph's Healthcare Hamilton

The small molecule chemical chaperone 4‐Phenylbutyrate inhibits epithelial‐to‐mesenchymal transition in human renal proximal tubular epithelial cells Conferences