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AFB1诱导小鼠肾功能损伤和足细胞损伤
小鼠每天给予0.75 mg/kg AFB1灌胃4周后，结果发现，与对照组相比，攻毒组小鼠的体质量显著下降，肾脏重量/体质量显著增加，小鼠血清中的肌酐、尿酸和尿素氮水平（表1）以及尿中白蛋白与肌酐的比值显著增加（图1A）。此外，肾小球足细胞平均足突宽度增加（图1B），大量糖原沉积（图1C），部分足细胞突触消失，且从肾小球基底膜外部脱离（图1D），以及肾小球裂隙隔膜蛋白nephrin和podocin显著减少（图1E和1G），表明AFB1导致肾小球足细胞损伤，结构完整性被破坏。AFB1也能够显著降低MPC-5细胞中nephrin和podocin的表达（图1F）。以上结果表明，AFB1可以诱导小鼠肾功能损伤和足细胞损伤。
表1 AFB1对小鼠体质量和肾功能的影响
图1 AFB1诱导小鼠肾功能损伤和足细胞损伤
AFB1诱导小鼠肾小球足细胞炎症
图2 AFB1诱导小鼠肾小球足细胞炎症
AFB1通过上调CXCR4表达激活TXNIP/NLRP3通路诱导肾小球足细胞炎症
图3 AFB1通过上调肾小球足细胞CXCR4表达激活TXNIP/NLRP3通路
图4 AFB1通过上调CXCR4表达激活TXNIP/NLRP3通路诱导肾小球足细胞炎症
AFB1通过下调miR-9激活CXCR4/TXNIP/NLRP3通路诱导小鼠肾小球足细胞炎症
图5 AFB1通过下调miR-9激活CXCR4/TXNIP/NLRP3通路诱导小鼠肾小球足细胞炎症
AFB1通过CXCR4/TXNIP/NLRP3通路下调miR-9表达诱导MPC-5足细胞炎症
图6 AFB1通过CXCR4/TXNIP/NLRP3通路下调miR-9表达诱导MPC-5足细胞炎症
AFB1通过促进RelA泛素依赖性蛋白水解下调miR-9表达
图7 AFB1通过促进RelA泛素依赖性蛋白水解下调miR-9表达
吴文达，男，合肥工业大学教授，博士生导师，黄山青年学者，赫拉德茨-克拉洛韦大学客座教授，江苏省“双创计划”科技副总。博士毕业于南京农业大学，2010-2013年、2015-2016年留学美国密歇根州立大学食品科学与人类营养系。担任本领域主流期刊Food Chem Toxicol、Front Immunol、Toxins特约编委和Lett Drug Design Discov编委。主要从事霉菌毒素与食品安全、肉品营养健康研究。主持国家自然科学基金面上项目、青年基金项目、江苏省自然科学基金、中国博士后科学基金特别资助等10余项。在Mol Cancer、Trends Food Sci Tech、J Hematol Oncol 和Arch Toxicol等国际著名期刊上发表第一或通讯作者SCI论文60余篇。申请和授权专利10余项，参与制订地方标准2项，参编“十三五”规划教材2部和英文论著1部。
Foodborne toxin Aflatoxin B1 induced glomerular podocyte inflammation through proteolysis of RelA, downregulation of miR-9 and CXCR4/TXNIP/NLRP3 pathway
Jie Zhanga,b, Shuang Yangb, Baocai Xuc, Zihui Qinc,d, Xinyi Guoc,d, Ben Weic,d, Qinghua Wue,f, Kamil Kucae, Tushuai Lig,h,*, Wenda Wuc,d,e,*
a School of Biology and Food Engineering, Changshu Institute of Technology, Suzhou 215500, China
b Center for Clinical Mass Spectrometry, School of Pharmaceutical Sciences, Soochow University, Suzhou 215123, China
c School of Food and Biological Engineering, Hefei University of Technology, Hefei 230009, China
d MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing 210095, China
e Department of Chemistry, Faculty of Science, University of Hradec Kralove, Hradec Kralove 50003, Czech Republic
f College of Life Science, Yangtze University, Jingzhou 434025, China
g Wuxi Medical College, Jiangnan University, Wuxi 214122, China
h Wuxi Translational Medicine Research Center and Jiangsu Translational Medicine Research Institute Wuxi Branch, Wuxi 214013, China
*Corresponding author.
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 AFB1 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.
ZHANG J, YANG S, XU B C, et al. Foodborne toxin Aflatoxin B1 induced glomerular podocyte inflammation through proteolysis of RelA, downregulation of miR-9 and CXCR4/TXNIP/NLRP3 pathway[J]. Food Science and Human Wellness, 2024, 13(4): 2289-2309. DOI:10.26599/FSHW.2022.9250191.
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