Abstract
Oxidative stress and apoptosis are involved in Ochratoxin A (OTA)-induced renal cytotoxicity. Apoptosis signal-regulating kinase 1 (ASK1) is a Mitogen-Activated Protein Kinase Kinase Kinase (MAPKKK, MAP3K) family member that plays an important role in oxidative stress-induced cell apoptosis. In this study, we performed RNA interference of ASK1 in HEK293 cells and employed an iTRAQ-based quantitative proteomics approach to globally investigate the regulatory mechanism of ASK1 in OTA-induced renal cytotoxicity. Our results showed that ASK1 knockdown alleviated OTA-induced ROS generation and Δψm loss and thus desensitized the cells to OTA-induced apoptosis. We identified 33 and 24 differentially expressed proteins upon OTA treatment in scrambled and ASK1 knockdown cells, respectively. Pathway classification and analysis revealed that ASK1 participated in OTA-induced inhibition of mRNA splicing, nucleotide metabolism, the cell cycle, DNA repair, and the activation of lipid metabolism. We concluded that ASK1 plays an essential role in promoting OTA-induced renal cytotoxicity.
Highlights
Oxidative stress and apoptosis are involved in Ochratoxin A (OTA)-induced renal cytotoxicity
Our results showed that Apoptosis signal-regulating kinase 1 (ASK1) knockdown alleviated OTA-induced reactive oxygen species (ROS) generation and Dym loss and desensitized the cells to OTA-induced apoptosis
Because OTA is capable of inducing oxidative stress and apoptosis, we speculated that ASK1 might be involved in OTA-induced apoptosis
Summary
Oxidative stress and apoptosis are involved in Ochratoxin A (OTA)-induced renal cytotoxicity. Apoptosis signal-regulating kinase 1 (ASK1) is a Mitogen-Activated Protein Kinase Kinase Kinase (MAPKKK, MAP3K) family member that plays an important role in oxidative stress-induced cell apoptosis. We performed RNA interference of ASK1 in HEK293 cells and employed an iTRAQ-based quantitative proteomics approach to globally investigate the regulatory mechanism of ASK1 in OTA-induced renal cytotoxicity. It has been reported that OTA might regulate cell fate via stimulating Mitogen Activated Protein Kinase (MAPK) family members, including ERK1/2, JNK, and p38 MAPK4,11–13. Apoptosis signal-regulating kinase 1 (ASK1) is an MAP3K family member that activates both the MKK4/MKK7-JNK and MKK3/MKK6-p38 pathways[16]. RNAi with iTRAQ-based quantitative proteomics, which is a more accurate quantification method with relatively high sensitivity and reproducibility[8,24]
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