Indoxyl sulfate induces oxidative stress and hypertrophy in cardiomyocytes by inhibiting the AMPK/UCP2 signaling pathway.

Abstract

As a typical protein-bound uremic toxin, indoxyl sulfate is considered to be able to induce cardiomyocytes hypertrophy by promoting oxidative stress in chronic kidney disease (CKD). Uncoupling protein 2 (UCP2), a member of the uncoupling protein family, may protect cardiomyocytes from oxidative stress by suppressing mitochondrial reactive oxygen species (ROS). In the present study, we aimed to determine whether UCP2 was involved in indoxyl sulfate-induced cardiomyocytes hypertrophy. We demonstrated that indoxyl sulfate could increase the ROS levels in a time and dose-dependent manner in cultured neonatal rat cardiomyocytes. Significant increases in [(3)H]-leucine incorporation, cell volume, and the mRNA expression levels of atrial natriuretic factor (ANF), brain natriuretic peptide (BNP), and beta myosin heavy chain (β-MHC) were detected in cardiomyocytes after treatement with indoxyl sulfate at the concentration of 500μM for 48h, accompanied by a decreased expression of UCP2. In contrast, cardiomyocytes transfected with the lentiviral vector carrying UCP2 gene were resistant to indoxyl sulfate-induced ROS production and cell hypertrophy. Additionally, indoxyl sulfate-induced UCP2 reduction was correlated with the inhibition of AMP-activated protein kinase (AMPK) activity, while pretreatment with AICAR, an AMPK activator, effectively attenuated indoxyl sulfate-induced UCP2 down-regulation and hypertrophy in cardiomyocytes. Taken together, these results suggest that indoxyl sulfate-induced cardiomyocytes hypertrophy was partly due to the inhibition of AMPK/UCP2 signaling and the enhancement of oxidative stress.

• Authors: Ke Yang, Xinli Xu, Ling Nie, Tangli Xiao, Xu Guan, Ting He, Yanlin Yu, Liang Liu, Yunjian Huang, Jingbo Zhang, Jinghong Zhao
• Journal: Toxicology letters (Toxicol Lett) Vol. 234 Issue 2 Pg. 110-9 (Apr 16 2015) ISSN: 1879-3169 [Electronic] Netherlands
• PMID: 25703824 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2015 Elsevier Ireland Ltd. All rights reserved.

Chemical References

• Ion Channels
• Mitochondrial Proteins
• Oxidants
• Protein Kinase Inhibitors
• Ucp2 protein, rat
• Uncoupling Protein 2
• AMP-Activated Protein Kinases
• Indican

Topics

• AMP-Activated Protein Kinases (antagonists & inhibitors, metabolism)
• Animals
• Animals, Newborn
• Cardiomegaly (chemically induced, enzymology, genetics, pathology)
• Cells, Cultured
• Dose-Response Relationship, Drug
• Down-Regulation
• Indican (toxicity)
• Ion Channels (genetics, metabolism)
• Mitochondrial Proteins (genetics, metabolism)
• Myocytes, Cardiac (drug effects, enzymology, pathology)
• Oxidants (toxicity)
• Oxidative Stress (drug effects)
• Protein Kinase Inhibitors (toxicity)
• Rats, Sprague-Dawley
• Signal Transduction (drug effects)
• Time Factors
• Transfection
• Uncoupling Protein 2