Abstract
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.
Highlights
Ochratoxin A (OTA) is a mycotoxin that occurs naturally in fungi such as Aspergillus spp. and Penicillium spp
Differential gene expression analysis of HK-2 cells following OTA treatment resulted in a total of 3193 differentially expressed genes (DEGs), of which 2224 were upregulated and 969 were downregulated (Figure 1)
To further explain the molecular function of DEGs identified in HK-2 cells exposed to OTA, Gene ontology (GO) and KEGG enrichment analysis were performed
Summary
Ochratoxin A (OTA) is a mycotoxin that occurs naturally in fungi such as Aspergillus spp. and Penicillium spp. OTA is known to exist in a variety of food groups such as cereals, cocoa, coffee, nuts, milk, beer, and wine, which are frequently consumed in daily life [1,2]. It is more stable to heat than other mycotoxins and is absorbed into the body through the gastrointestinal tract with food consumption. Ingested OTA is rapidly absorbed through the jejunum with a bioavailability of 97% [4]. OTA binds strongly to albumin in serum and has a very long half-life, eventually accumulating in the body [5]. OTA is one of the most harmful fungal toxins and is classified in Group 2B as a possible human carcinogen by the International Agency for Research on Cancer [6].
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