TY - JOUR
T1 - Renal toxicity through AhR, PXR, and Nrf2 signaling pathway activation of ochratoxin A-induced oxidative stress in kidney cells
AU - Lee, Hyun Jung
AU - Pyo, Min Cheol
AU - Shin, Hye Soo
AU - Ryu, Dojin
AU - Lee, Kwang Won
PY - 2018/12/1
Y1 - 2018/12/1
N2 - Because ochratoxin A (OTA) is widely found in foods, people are susceptible to OTA exposure. The mechanism leading to renal toxicity induced by OTA remains unclear. The aim of this study was to investigate OTA-induced toxicity in human proximal tubule HK-2 cells. OTA decreased cell viability, and the expression of kidney injury molecule-1 (KIM-1), a kidney damage marker, was increased when HK-2 cells were exposed to OTA. Additionally, OTA treatment of cells increased intracellular reactive oxygen species and malondialdehyde and decreased glutathione levels. OTA-treated cells induced the aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) genes followed by induction of the cytochrome P450 1A1 (CYP1A1), CYP1A2, and CYP3A4 genes representing phase I enzyme. The mRNA expression of phase II enzymes such as heme oxygenase-1, nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase 1, and glutamate cysteine ligase catalytic subunit were upregulated by activation of NF-E2-related factor 2 (Nrf2) translocation by treatment with OTA. The response of OTA-orally administered mice also showed marked increases in these enzymes as well as KIM-1. These results indicate that OTA induces phase I and II enzymes through the AhR, PXR, and Nrf2 signaling pathways in HK-2 cells, which may lead to modulation of proximal tubule injury.
AB - Because ochratoxin A (OTA) is widely found in foods, people are susceptible to OTA exposure. The mechanism leading to renal toxicity induced by OTA remains unclear. The aim of this study was to investigate OTA-induced toxicity in human proximal tubule HK-2 cells. OTA decreased cell viability, and the expression of kidney injury molecule-1 (KIM-1), a kidney damage marker, was increased when HK-2 cells were exposed to OTA. Additionally, OTA treatment of cells increased intracellular reactive oxygen species and malondialdehyde and decreased glutathione levels. OTA-treated cells induced the aryl hydrocarbon receptor (AhR) and pregnane X receptor (PXR) genes followed by induction of the cytochrome P450 1A1 (CYP1A1), CYP1A2, and CYP3A4 genes representing phase I enzyme. The mRNA expression of phase II enzymes such as heme oxygenase-1, nicotinamide adenine dinucleotide phosphate-quinone oxidoreductase 1, and glutamate cysteine ligase catalytic subunit were upregulated by activation of NF-E2-related factor 2 (Nrf2) translocation by treatment with OTA. The response of OTA-orally administered mice also showed marked increases in these enzymes as well as KIM-1. These results indicate that OTA induces phase I and II enzymes through the AhR, PXR, and Nrf2 signaling pathways in HK-2 cells, which may lead to modulation of proximal tubule injury.
KW - Aryl hydrocarbon receptor
KW - Kidney injury
KW - NF-E2-related factor 2
KW - Ochratoxin A
KW - Oxidative stress
KW - Pregnane X receptor
UR - http://www.scopus.com/inward/record.url?scp=85054469046&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85054469046&partnerID=8YFLogxK
U2 - 10.1016/j.fct.2018.10.004
DO - 10.1016/j.fct.2018.10.004
M3 - Article
C2 - 30291945
AN - SCOPUS:85054469046
VL - 122
SP - 59
EP - 68
JO - Food and Chemical Toxicology
JF - Food and Chemical Toxicology
SN - 0278-6915
ER -