4.6 Article

ATF6 pathway of unfolded protein response mediates advanced oxidation protein product-induced hypertrophy and epithelial-to-mesenchymal transition in HK-2 cells

Journal

MOLECULAR AND CELLULAR BIOCHEMISTRY
Volume 407, Issue 1-2, Pages 197-207

Publisher

SPRINGER
DOI: 10.1007/s11010-015-2469-0

Keywords

Unfolded protein response (UPR); Advanced oxidation protein products (AOPPs); Epithelial-to-mesenchymal transition (EMT); Hypertrophy; Endoplasmic reticulum stress

Categories

Funding

  1. Natural Science Foundation of Guangdong Province [10151051501000030, S2011010004053, S2011040003566]
  2. Science and Technical Plan of Guangzhou, Guangdong, China [11C22120703]
  3. Science and Technical Plan of Guangdong, China [2013B021800149]
  4. National Natural Science Foundation of China [81202842]

Ask authors/readers for more resources

Advanced oxidation protein products (AOPPs) accelerate the progression of chronic kidney disease. We previously demonstrated that AOPPs induce hypertrophy and epithelial-to-mesenchymal transition (EMT) in human proximal tubular cells (HK-2 cells) through induction of endoplasmic reticulum (ER) stress. However, which pathway of unfolded protein response (UPR) induced by ER stress plays crucial roles in this process remains unclear. In this study, we investigated the roles of the protein kinase RNA-like ER kinase (PERK), activating transcription factor 6 (ATF6), and inositol-requiring enzyme 1 (IRE1) pathways of UPR in this process in HK-2 cells. AOPP treatment induced the overexpression of cleaved ATF6 and spliced form of X-box binding protein-1, and induced the phosphorylation of PERK, eukaryotic translation initiation factor 2 alpha and IRE1. Furthermore, silencing of ATF6 increased E-cadherin and zonula occludens-1 expression, lowered the expression of vimentin, and downregulated total protein content, whereas knockdown of PERK or IRE1 resulted in no difference compared with the scramble siRNA-transfected cells. AOPP-induced phosphorylation of Src, which was reproduced by thapsigargin, an inducer of ER stress, was partly reversed by salubrinal, an inhibitor of ER stress. Furthermore, the Src inhibitor saracatinib effectively blocked AOPP-induced phosphorylation of Src, activation of ER stress, hypertrophy, and EMT in HK-2 cells. Collectively, our results indicate that AOPPs induce the PERK, ATF6, and IRE1 pathways of UPR, and the ATF6 pathway rather than the other two pathways mediates AOPP-induced HK-2-cell hypertrophy and EMT. We also suggest that the ER stress involved in this process is likely mediated by the activation of Src kinase.

Authors

I am an author on this paper
Click your name to claim this paper and add it to your profile.

Reviews

Primary Rating

4.6
Not enough ratings

Secondary Ratings

Novelty
-
Significance
-
Scientific rigor
-
Rate this paper

Recommended

No Data Available
No Data Available