Manganese induces podocyte injury through regulating MTDH/ALKBH5/NLRP10 axis: Combined analysis at epidemiology and molecular biology levels

Qiuju Liang; Jiajun Jing; Huiming He; Xiaofeng Huang; Jianing Liu; Mingjun Wang; Zijuan Qi; Li'e Zhang; Ziang Huang; Yuanliang Yan; Sijin Liu; Ming Gao; Yunfeng Zou

Environment International (May 2024)

Manganese induces podocyte injury through regulating MTDH/ALKBH5/NLRP10 axis: Combined analysis at epidemiology and molecular biology levels

Qiuju Liang,
Jiajun Jing,
Huiming He,
Xiaofeng Huang,
Jianing Liu,
Mingjun Wang,
Zijuan Qi,
Li'e Zhang,
Ziang Huang,
Yuanliang Yan,
Sijin Liu,
Ming Gao,
Yunfeng Zou

Affiliations

Qiuju Liang: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
Jiajun Jing: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; School of Public Health, Guangxi Medical University, Nanning 530021, China
Huiming He: School of Public Health, Guangxi Medical University, Nanning 530021, China; Institute of Parasitic Disease Control and Prevention, Guangxi Zhuang Autonomous Region Center for Disease Control and Prevention, Nanning 530021, China
Xiaofeng Huang: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100085, China
Jianing Liu: School of Public Health, Guangxi Medical University, Nanning 530021, China
Mingjun Wang: Department of Nephrology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China
Zijuan Qi: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; Shandong First Medical University & Shandong Academy of Medical Sciences, Ji’nan 250014, Shandong, China
Li'e Zhang: School of Public Health, Guangxi Medical University, Nanning 530021, China
Ziang Huang: Department of Mathematics, University of California at Davis, CA 95616, USA
Yuanliang Yan: Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China
Sijin Liu: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100085, China
Ming Gao: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China; College of Resources and Environment, University of Chinese Academy of Sciences, Beijing 100085, China; Corresponding authors at: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China (Ming Gao).
Yunfeng Zou: School of Public Health, Guangxi Medical University, Nanning 530021, China; Corresponding authors at: State Key Laboratory of Environmental Chemistry and Ecotoxicology, Research Center for Eco-Environmental Sciences, Chinese Academy of Sciences, Beijing 100085, China (Ming Gao).

Journal volume & issue: Vol. 187
p. 108672

Abstract

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Manganese (Mn) is an essential micronutrient required for various biological processes but excess exposure to Mn can cause neurotoxicity. However, there are few reports regarding the toxicity effect of Mn on the kidney as well as the underlying molecule mechanism. Herein, in vivo experiments were adopted to assess the toxicity effects associated with Mn, and found that chronic Mn treatment induced the injury of glomerular podocytes but not renal tubule in rats. Genome-wide CRISPR/Cas9 knockout screen was then employed to explore the biotargets of the toxic effect of Mn on podocytes. Through functional analyses of the enriched candidate genes, NLRP10 was found to be significantly up-regulated and mediated Mn-induced podocyte apoptosis. Further mechanism investigation revealed that NLRP10 expression was regulated by demethylase AlkB homolog 5 (ALKBH5) in an m6A-dependent fashion upon Mn treatment. Moreover, Mn could directly bind to Metadherin (MTDH) and promoted its combination with ALKBH5 to promote NLRP10 expression and cell apoptosis. Finally, logistic regressions, restricted cubic spline regressions and uniform cubic B-spline were used to investigate the association between Mn exposure and the risk of chronic kidney disease (CKD). A U-shaped nonlinear relationship between CKD risk and plasma Mn level, and a positive linear relationship between CKD risk and urinary Mn levels was found in our case-control study. To sum up, our findings illustrated that m6A-dependent NLRP10 regulation is indispensable for podocyte apoptosis and nephrotoxicity induced by Mn, providing fresh insight into understanding the health risk of Mn and a novel target for preventing renal injury in Mn-intoxicated patients.

Published in Environment International

ISSN: 0160-4120 (Print)
Publisher: Elsevier
Country of publisher: United Kingdom
LCC subjects: Geography. Anthropology. Recreation: Environmental sciences
Website: https://www.journals.elsevier.com/environment-international

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