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

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

  • Environ Int. 2024 Apr 18:187:108672. doi: 10.1016/j.envint.2024.108672.
Qiuju Liang 1,  Jiajun Jing 2,  Huiming He 3,  Xiaofeng Huang 4,  Jianing Liu 5,  Mingjun Wang 6,  Zijuan Qi 7,  Li'e Zhang 5,  Ziang Huang 8,  Yuanliang Yan 9,  Sijin Liu 4,  Ming Gao 10,  Yunfeng Zou 11
Affiliations

Affiliations

  • 1 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.
  • 2 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.
  • 3 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.
  • 4 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.
  • 5 School of Public Health, Guangxi Medical University, Nanning 530021, China.
  • 6 Department of Nephrology, The First Affiliated Hospital of Guangxi Medical University, Nanning 530021, China.
  • 7 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.
  • 8 Department of Mathematics, University of California at Davis, CA 95616, USA.
  • 9 Department of Pharmacy, Xiangya Hospital, Central South University, Changsha 410008, Hunan, China.
  • 10 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. Electronic address: minggao@rcees.ac.cn.
  • 11 School of Public Health, Guangxi Medical University, Nanning 530021, China. Electronic address: zouyunfeng@gxmu.edu.cn.
PMID: 38648691 DOI: 10.1016/j.envint.2024.108672
Abstract

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.

Keywords

CRISPR/Cas9 knockout screen; M(6)A; Manganese; NLRP10; Podocyte injury.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z