Foodborne toxin Aflatoxin B1 induced glomerular podocyte inflammation through proteolysis of RelA,downregulation of miR-9 and CXCR4/TXNIP/NLRP3 pathway

Jie Zhang ¹Shuang Yang ²Baocai Xu ³Zihui Qin ⁴Xinyi Guo ⁴Ben Wei ⁴Qinghua Wu ⁵Kamil Kuca ⁶Tushuai Li ⁷Wenda Wu⁸

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作者信息

1. School of Biology and Food Engineering,Changshu Institute of Technology,Suzhou 215500,China;Center for Clinical Mass Spectrometry,School of Pharmaceutical Sciences,Soochow University,Suzhou 215123,China
2. Center for Clinical Mass Spectrometry,School of Pharmaceutical Sciences,Soochow University,Suzhou 215123,China
3. School of Food and Biological Engineering,Hefei University of Technology,Hefei 230009,China
4. School of Food and Biological Engineering,Hefei University of Technology,Hefei 230009,China;MOE Joint International Research Laboratory of Animal Health and Food Safety,College of Veterinary Medicine,Nanjing Agricultural University,Nanjing 210095,China
5. Department of Chemistry,Faculty of Science,University of Hradec Kralove,Hradec Kralove 50003,Czech Republic;College of Life Science,Yangtze University,Jingzhou 434025,China
6. Department of Chemistry,Faculty of Science,University of Hradec Kralove,Hradec Kralove 50003,Czech Republic
7. Wuxi Medical College,Jiangnan University,Wuxi 214122,China;Wuxi Translational Medicine Research Center and Jiangsu Translational Medicine Research Institute Wuxi Branch,Wuxi 214013,China
8. School of Food and Biological Engineering,Hefei University of Technology,Hefei 230009,China;MOE Joint International Research Laboratory of Animal Health and Food Safety,College of Veterinary Medicine,Nanjing Agricultural University,Nanjing 210095,China;Department of Chemistry,Faculty of Science,University of Hradec Kralove,Hradec Kralove 50003,Czech Republic
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Abstract

Aflatoxin B1(AFB1)is a naturally-occurring mycotoxin and recognized as the most toxic foodborne toxin,particularly causing damages to kidney.Glomerular podocytes are terminally differentiated epithelial cells.AFB1 induces podocyte inflammation,proteinuria and renal dysfunction.Studying the mechanism of AFB1-induced podocyte inflammation and murine kidney dysfunction,we detected that AFB,increased ubiquitin-dependent degradation of the transcription factor RelA through enhanced interaction of RelA with E3 ubiquitin ligase tripartite motif containing 7(TRIM7)in mouse podocyte clone-5(MPC-5)and mouse glomeruli.Reduction of RelA resulted in decreasing microRNA-9(miR-9)and activating the chemokine receptor 4(CXCR4),thioredoxin interacting protein(TXNIP),and NOD-like receptor pyrin domain-containing 3(NLRP3)signaling axis(CXCR4/TXNIP/NLRP3 pathway),leading to podocyte inflammation.We also determined that downregulation of miR-9 led to CXCR4 expression and the downstream TXNIP/NLRP3 pathway activation.Overexpression of miR-9 or deletion of CXCR4 suppressed AFB1-induced CXCR4/TXNIP/NLRP3 pathway,resulting in alleviating podocyte inflammation and kidney dysfunction.Our findings indicated that ubiquitin-dependent proteolysis of RelA,downregulation of miR-9,and activation of CXCR4/TXNIP/NLRP3 pathway played an essential role in AFB1-induced glomerular podocyte inflammation.Our study revealed a novel mechanism,via RelA,for the control of AFB1's nephrotoxicity,leading to an effective protection of food safety and public health.

Key words

Aflatoxin B1/Podocyte inflammation/miRNA-9/Chemokine(C-X-C motif)receptor 4/RelA ubiquitin-dependent degradation

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基金项目

Suzhou Science and Technology Council(SNG201907)

Universities Natural Science Foundation of Jiangsu Province(20KJB330002)

General Program of China Postdoctoral Science Foundation(2022M711369)

Startup Funding of Soochow University,Jiangsu Province-Suzhou Science and Technology Planning Project(SL T201917)

国家自然科学基金(32172922)

国家自然科学基金(31972741)

江苏省自然科学基金(BK20211216)

江苏省自然科学基金(BK20221091)

Startup Funding of Hefei University of Technology(13020-03712022058)

China-CEEC Joint University Education Project(202010)

Excellence Project PrF UHK(2217/2022-2023)

出版年

2024

食品科学与人类健康(英文)

CSTPCD

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参考文献量65

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