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赭曲霉毒素A通过HIF-1α/miR-155-5p通路诱导肾脏内质网应激和纤维化。

Ochratoxin A induces endoplasmic reticulum stress and fibrosis in the kidney via the HIF-1α/miR-155-5p link.

作者信息

Yang Seon Ah, Rhee Kyu Hyun, Yoo Hee Joon, Pyo Min Cheol, Lee Kwang-Won

机构信息

Department of Biotechnology, College of Life Sciences and Biotechnology, Korea University, 02841 Seoul, the Republic of Korea.

Department of Food Bioscience and Technology, College of Life Sciences and Biotechnology, Korea University, 02841 Seoul, the Republic of Korea.

出版信息

Toxicol Rep. 2023 Jan 18;10:133-145. doi: 10.1016/j.toxrep.2023.01.006. eCollection 2023.

DOI:10.1016/j.toxrep.2023.01.006
PMID:36714464
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC9879730/
Abstract

Ochratoxin A (OTA) is a ubiquitous fungal toxin found in agricultural products and foods that is toxic to both humans and animals. OTA mainly affects kidney, but the mechanisms underlying OTA-induced nephrotoxicity remain not fully understood. MicroRNA (miRNA) is involved in key cellular processes. The toxic mechanism and regulatory effects of miRNAs on OTA toxicity in kidney, and particularly the role of HIFα-1/miR-155-5p on OTA-caused ER stress and fibrosis, were investigated in this study. OTA induced hypoxia-like conditions such as ER stress and fibrosis in HK-2 cells and renal tissues via modulating HIF-1α, which was followed by regulation of ER stress-related proteins (GRP78 and ATF-4), as well as fibrosis-related markers (fibronectin, α-SMA, and E-cadherin). Notably, a total of 62 miRNAs showed significant differential expression in kidney of OTA-treated mice. Under OTA exposure, HIF-1α enhanced miR-155-5p expression, causing ER stress and fibrosis in HK-2 cells. HIF-1α knockdown decreased OTA-induced miR-155-5p expression as well as ER stress and fibrotic responses, whereas miR-155-5p overexpression restored this. Our data suggest that OTA enhances ER stress and fibrosis in the kidney through upregulating the HIF-1α/miR-155-5p link.

摘要

赭曲霉毒素A（OTA）是一种存在于农产品和食品中的普遍存在的真菌毒素，对人和动物均有毒性。OTA主要影响肾脏，但其诱导肾毒性的机制仍未完全阐明。微小RNA（miRNA）参与关键的细胞过程。本研究探讨了miRNA对肾脏中OTA毒性的作用机制和调控作用，尤其是HIFα-1/miR-155-5p在OTA引起的内质网应激和纤维化中的作用。OTA通过调节HIF-1α在HK-2细胞和肾组织中诱导内质网应激和纤维化等类似缺氧的状况，随后调节内质网应激相关蛋白（GRP78和ATF-4）以及纤维化相关标志物（纤连蛋白、α-SMA和E-钙黏蛋白）。值得注意的是，共有62种miRNA在OTA处理的小鼠肾脏中表现出显著差异表达。在OTA暴露下，HIF-1α增强miR-155-5p的表达，导致HK-2细胞内质网应激和纤维化。HIF-1α敲低降低了OTA诱导的miR-155-5p表达以及内质网应激和纤维化反应，而miR-155-5p过表达则恢复了这种情况。我们的数据表明，OTA通过上调HIF-1α/miR-155-5p联系增强肾脏内质网应激和纤维化。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/9879730/63ab8926556e/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/9879730/543d7a9994c5/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/9879730/43f96c3b8d16/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/9879730/ef5e31c67ee7/gr2a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/9879730/39622953622e/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/9879730/b3b1c1d63af2/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/9879730/a7a5669ee6e1/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/9879730/8a3359e2190d/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/9879730/63ab8926556e/gr7.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/9879730/543d7a9994c5/ga1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/9879730/43f96c3b8d16/gr1.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/9879730/ef5e31c67ee7/gr2a.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/9879730/39622953622e/gr3.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/9879730/b3b1c1d63af2/gr4.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/9879730/a7a5669ee6e1/gr5.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/9879730/8a3359e2190d/gr6.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/46e0/9879730/63ab8926556e/gr7.jpg

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