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Transcriptome Analysis Reveals the AhR, Smad2/3, and HIF-1α Pathways as the Mechanism of Ochratoxin A Toxicity in Kidney Cells

Ochratoxin A (OTA) is a mycotoxin occurring in foods consumed by humans. Recently, there has been growing global concern regarding OTA toxicity. The main target organ of OTA is the kidney, but the mechanism underlying renal toxicity is not well known. In this study, human-derived proximal tubular ep...

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Autores principales: Pyo, Min Cheol, Choi, In-Geol, Lee, Kwang-Won
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999264/
https://www.ncbi.nlm.nih.gov/pubmed/33800744
http://dx.doi.org/10.3390/toxins13030190
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author Pyo, Min Cheol
Choi, In-Geol
Lee, Kwang-Won
author_facet Pyo, Min Cheol
Choi, In-Geol
Lee, Kwang-Won
author_sort Pyo, Min Cheol
collection PubMed
description Ochratoxin A (OTA) is a mycotoxin occurring in foods consumed by humans. Recently, there has been growing global concern regarding OTA toxicity. The main target organ of OTA is the kidney, but the mechanism underlying renal toxicity is not well known. In this study, human-derived proximal tubular epithelial cells, HK-2 cells, were used for RNA-sequencing (RNA-seq) and transcriptome analysis. In total, 3193 differentially expressed genes were identified upon treatment with 200 nM OTA in HK-2 cells; of these, 2224 were upregulated and 969 were downregulated. Transcriptome analysis revealed that OTA significantly affects hypoxia, epithelial-mesenchymal transition (EMT), apoptosis, and xenobiotic metabolism pathways in kidney cells. Quantitative real-time PCR analysis showed gene expression patterns similar to RNA-seq analysis. Expression of EMT markers (E-cadherin and fibronectin), apoptosis markers (caspase-3 and Bax), and kidney injury molecule-1 (KIM-1) was suppressed by inhibiting AhR expression using siRNA, and the related transcription factors, Smad2/3, and HIF-1α were downregulated. Smad2/3 suppression with siRNA could inhibit fibronetcin, caspase-3, Bax, and KIM-1 expression. Fibronetcin, caspase-3, Bax, and KIM-1 expression could be increased with HIF-1α suppression with siRNA. Taken together, these findings suggest that OTA-mediated kidney toxicity via the AhR-Smad2/3-HIF-1α signaling pathways leads to induction of EMT, apoptosis, and kidney injury.
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spelling pubmed-79992642021-03-28 Transcriptome Analysis Reveals the AhR, Smad2/3, and HIF-1α Pathways as the Mechanism of Ochratoxin A Toxicity in Kidney Cells Pyo, Min Cheol Choi, In-Geol Lee, Kwang-Won Toxins (Basel) Article Ochratoxin A (OTA) is a mycotoxin occurring in foods consumed by humans. Recently, there has been growing global concern regarding OTA toxicity. The main target organ of OTA is the kidney, but the mechanism underlying renal toxicity is not well known. In this study, human-derived proximal tubular epithelial cells, HK-2 cells, were used for RNA-sequencing (RNA-seq) and transcriptome analysis. In total, 3193 differentially expressed genes were identified upon treatment with 200 nM OTA in HK-2 cells; of these, 2224 were upregulated and 969 were downregulated. Transcriptome analysis revealed that OTA significantly affects hypoxia, epithelial-mesenchymal transition (EMT), apoptosis, and xenobiotic metabolism pathways in kidney cells. Quantitative real-time PCR analysis showed gene expression patterns similar to RNA-seq analysis. Expression of EMT markers (E-cadherin and fibronectin), apoptosis markers (caspase-3 and Bax), and kidney injury molecule-1 (KIM-1) was suppressed by inhibiting AhR expression using siRNA, and the related transcription factors, Smad2/3, and HIF-1α were downregulated. Smad2/3 suppression with siRNA could inhibit fibronetcin, caspase-3, Bax, and KIM-1 expression. Fibronetcin, caspase-3, Bax, and KIM-1 expression could be increased with HIF-1α suppression with siRNA. Taken together, these findings suggest that OTA-mediated kidney toxicity via the AhR-Smad2/3-HIF-1α signaling pathways leads to induction of EMT, apoptosis, and kidney injury. MDPI 2021-03-06 /pmc/articles/PMC7999264/ /pubmed/33800744 http://dx.doi.org/10.3390/toxins13030190 Text en © 2021 by the authors. https://creativecommons.org/licenses/by/4.0/Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) ).
spellingShingle Article
Pyo, Min Cheol
Choi, In-Geol
Lee, Kwang-Won
Transcriptome Analysis Reveals the AhR, Smad2/3, and HIF-1α Pathways as the Mechanism of Ochratoxin A Toxicity in Kidney Cells
title Transcriptome Analysis Reveals the AhR, Smad2/3, and HIF-1α Pathways as the Mechanism of Ochratoxin A Toxicity in Kidney Cells
title_full Transcriptome Analysis Reveals the AhR, Smad2/3, and HIF-1α Pathways as the Mechanism of Ochratoxin A Toxicity in Kidney Cells
title_fullStr Transcriptome Analysis Reveals the AhR, Smad2/3, and HIF-1α Pathways as the Mechanism of Ochratoxin A Toxicity in Kidney Cells
title_full_unstemmed Transcriptome Analysis Reveals the AhR, Smad2/3, and HIF-1α Pathways as the Mechanism of Ochratoxin A Toxicity in Kidney Cells
title_short Transcriptome Analysis Reveals the AhR, Smad2/3, and HIF-1α Pathways as the Mechanism of Ochratoxin A Toxicity in Kidney Cells
title_sort transcriptome analysis reveals the ahr, smad2/3, and hif-1α pathways as the mechanism of ochratoxin a toxicity in kidney cells
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7999264/
https://www.ncbi.nlm.nih.gov/pubmed/33800744
http://dx.doi.org/10.3390/toxins13030190
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