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The role of AMP‐activated protein kinase α1‐mediated endoplasmic reticulum stress in alleviating the toxic effect of uremic toxin indoxyl sulfate on vascular endothelial cells by Klotho
Author(s) -
Chen Cheng,
Wu Lin,
Xie Caidie,
Zhao Xiufen,
Mao Huijuan,
Xing Changying
Publication year - 2021
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.4135
Subject(s) - klotho , ampk , endoplasmic reticulum , protein kinase a , microbiology and biotechnology , umbilical vein , chemistry , unfolded protein response , kinase , medicine , kidney , biochemistry , biology , in vitro
Recently, the Klotho protein (Klotho) has received substantial attention as protective factor against cardiovascular complications of chronic kidney disease (CKD). However, the direct effect and mechanism of Klotho on endothelial cells injury are not well‐known. In this study, we incubated human vein umbilical endothelial cells (HUVECs) with uremic toxin indoxyl sulfate (IS) to mimic CKD internal environment and investigated the direct effect of Klotho on the HUVECs injury induced by IS and to explore the mechanism in this process. We found IS inhibited cell viability, increased endoplasmic reticulum stress, and mediated apoptosis of HUVECs. Treatment with Klotho significantly attenuated IS‐induced above effects. Furthermore, Klotho alleviated the IS toxic effect on HUVECs via promoting AMP‐activated protein kinase (AMPK) α1 phosphorylation instead of directly upregulating AMPKα1, which could be partly blocked by AMPK pathway inhibitor‐Compound C. In addition, Klotho also inhibited intercellular adhesion molecule‐1 (ICAM‐1) and vascular cell adhesion molecule‐1 (VCAM‐1) expression induced by IS. Altogether, these results indicated that Klotho can protect HUVECs from IS‐induced injury by alleviating AMPKα1‐mediated endoplasmic reticulum stress.