Study on the Correlation Between Regulatory Proteins of N-methyladenosine and Oxidative Damage in Cadmium-induced Renal Injury

Overview

Journal Biol Trace Elem Res

Date 2022 Jul 6

PMID 35794303

Authors

Yifei Sun

Guofen Liu

Mengzhu Li

Lei Wang

Zuoshun He

Shiyan Gu

Affiliations

Soon will be listed here.

Abstract

As a common environmental heavy metal pollutant, cadmium has been well evidenced to cause kidney damage; yet, the underlying mechanisms are still not fully clarified. In this study, cell viability of human renal tubular epithelial cell (HK-2) was determined by CCK-8 assay after treatment with CdSO. Then, apoptotic morphology of cells was observed by Hoechst staining and level of reactive oxygen species (ROS) was detected by fluorescent probes. Subsequently, mRNA levels of Nrf2, HO-1, mA methyltransferases (METTL3, METTL14, METTL16, WATP), mA demethylases (FTO, ALKBH5), mA methyl-binding proteins (YTHDF1, YTHDF2, YTHDF3, YTHDC1, YTHDC2) were detected by real-time polymerase chain reaction (RT-PCR), closely followed by correlation analysis between Nrf2 mRNA levels and mA methyltransferases and demethylases. Lastly, protein expressions of Nrf2, METTL3, and FTO were tested by western blotting assay. The detection results demonstrated that the treatment of CdSO decreased viability while increased apoptosis rate. The Nrf2 mRNA level in CdSO-treated cells was significantly increased when compared with that in the control cells, and the HO-1 mRNA level elevated with the increasing of CdSO concentrations. In addition, mRNA levels of METTL3, METTL14, METTL16, WTAP, FTO, and methyl-binding proteins in CdSO-treated cells were all higher than those in corresponding control cells. Further determination showed that protein expressions of Nrf2, METTL3, and FTO were also upregulation under the treatment of CdSO. Lastly, correlation analysis indicated that mRNA level of Nrf2 was positively correlated with mRNA levels of mA methyltransferases and demethylases. In a word, our results demonstrated that the molecular changes of Nrf2 signaling pathway are correlated with the levels of mA regulatory proteins, suggesting that there may be a regulatory relationship between Nrf2 signaling pathway and mA regulatory proteins in the process of cadmium-induced renal cell cytotoxicity.

Citing Articles

RNA mA involves in regulation of oxidative stress and apoptosis may via NF-kB pathway in cadmium-induced lung cells.

Zhang N, Yang J, Zhao Y, Li W, Zhao B, Li R Cell Death Discov. 2025; 11(1):4.

PMID: 39794323 PMC: 11723944. DOI: 10.1038/s41420-024-02284-w.

Methyltransferase-like 3 represents a prospective target for the diagnosis and treatment of kidney diseases.

Song B, Wu X, Zeng Y Hum Genomics. 2024; 18(1):125.

PMID: 39538346 PMC: 11562609. DOI: 10.1186/s40246-024-00692-8.

Multifaceted bioinformatic analysis of m6A-related ferroptosis and its link with gene signatures and tumour-infiltrating immune cells in gliomas.

Yang Y, Hao L, Guiyang L, Haozhe P J Cell Mol Med. 2024; 28(17):e70060.

PMID: 39248438 PMC: 11382363. DOI: 10.1111/jcmm.70060.

Astragalus polysaccharide alleviates IL-13-induced oxidative stress injury in nasal epithelial cells by inhibiting WTAP-mediated FBXW7 mA modification.

Cui W, Jin Z, Lin H, Wang B, Chen G, Cheng Y Toxicol Res (Camb). 2024; 13(4):tfae099.

PMID: 38957784 PMC: 11215160. DOI: 10.1093/toxres/tfae099.

Changes of mA Regulatory Proteins and Nrf2 Signaling Molecules in Liver Tissue of Type 2 Diabetes Mellitus Rats.

Wang N, Yang J, Liu X, Liu G, He Z, Gu S Cell Biochem Biophys. 2024; 82(3):2217-2226.

PMID: 38822202 DOI: 10.1007/s12013-024-01331-8.

References

Chen C, Han X, Wang G, Liu D, Bao L, Jiao C . Nrf2 deficiency aggravates the kidney injury induced by subacute cadmium exposure in mice. Arch Toxicol. 2021; 95(3):883-893. DOI: 10.1007/s00204-020-02964-3. View

Hao R, Song X, Sun-Waterhouse D, Tan X, Li F, Li D . MiR-34a/Sirt1/p53 signaling pathway contributes to cadmium-induced nephrotoxicity: A preclinical study in mice. Environ Pollut. 2021; 282:117029. DOI: 10.1016/j.envpol.2021.117029. View

Ahmed O, Xu M, Zhou F, Wein A, Upadhya G, Ye L . NRF2 assessment in discarded liver allografts: A role in allograft function and salvage. Am J Transplant. 2021; 22(1):58-70. DOI: 10.1111/ajt.16789. View

Mei Z, Du L, Liu X, Chen X, Tian H, Deng Y . Diosmetin alleviated cerebral ischemia/reperfusion injury and by inhibiting oxidative stress the SIRT1/Nrf2 signaling pathway. Food Funct. 2021; 13(1):198-212. DOI: 10.1039/d1fo02579a. View

Choudhury C, Mazumder R, Kumar R, Dhar B, Sengupta M . Cadmium induced oxystress alters Nrf2-Keap1 signaling and triggers apoptosis in piscine head kidney macrophages. Aquat Toxicol. 2021; 231:105739. DOI: 10.1016/j.aquatox.2020.105739. View

Zaccara S, Ries R, Jaffrey S . Reading, writing and erasing mRNA methylation. Nat Rev Mol Cell Biol. 2019; 20(10):608-624. DOI: 10.1038/s41580-019-0168-5. View

Zhuang C, Zhuang C, Luo X, Huang X, Yao L, Li J . N6-methyladenosine demethylase FTO suppresses clear cell renal cell carcinoma through a novel FTO-PGC-1α signalling axis. J Cell Mol Med. 2019; 23(3):2163-2173. PMC: 6378205. DOI: 10.1111/jcmm.14128. View

Arumugam T, Ghazi T, Chuturgoon A . Fumonisin B alters global m6A RNA methylation and epigenetically regulates Keap1-Nrf2 signaling in human hepatoma (HepG2) cells. Arch Toxicol. 2021; 95(4):1367-1378. DOI: 10.1007/s00204-021-02986-5. View

10.

Zhao T, Wang J, Shen L, Long C, Liu B, Wei Y . Increased m6A RNA modification is related to the inhibition of the Nrf2-mediated antioxidant response in di-(2-ethylhexyl) phthalate-induced prepubertal testicular injury. Environ Pollut. 2020; 259:113911. DOI: 10.1016/j.envpol.2020.113911. View

11.

Qu T, Mou Y, Dai J, Zhang X, Li M, Gu S . Changes and relationship of N-methyladenosine modification and long non-coding RNAs in oxidative damage induced by cadmium in pancreatic β-cells. Toxicol Lett. 2021; 343:56-66. DOI: 10.1016/j.toxlet.2021.02.014. View

12.

Das S, Dewanjee S, Dua T, Joardar S, Chakraborty P, Bhowmick S . Carnosic Acid Attenuates Cadmium Induced Nephrotoxicity by Inhibiting Oxidative Stress, Promoting Nrf2/HO-1 Signalling and Impairing TGF-β1/Smad/Collagen IV Signalling. Molecules. 2019; 24(22). PMC: 6891359. DOI: 10.3390/molecules24224176. View

13.

Ge J, Zhang C, Sun Y, Zhang Q, Lv M, Guo K . Cadmium exposure triggers mitochondrial dysfunction and oxidative stress in chicken (Gallus gallus) kidney via mitochondrial UPR inhibition and Nrf2-mediated antioxidant defense activation. Sci Total Environ. 2019; 689:1160-1171. DOI: 10.1016/j.scitotenv.2019.06.405. View

14.

Genchi G, Sinicropi M, Lauria G, Carocci A, Catalano A . The Effects of Cadmium Toxicity. Int J Environ Res Public Health. 2020; 17(11). PMC: 7312803. DOI: 10.3390/ijerph17113782. View

15.

Fujiki K, Inamura H, Sugaya T, Matsuoka M . Blockade of ALK4/5 signaling suppresses cadmium- and erastin-induced cell death in renal proximal tubular epithelial cells via distinct signaling mechanisms. Cell Death Differ. 2019; 26(11):2371-2385. PMC: 6889492. DOI: 10.1038/s41418-019-0307-8. View

16.

Ge Z, Diao H, Ji X, Liu Q, Zhang X, Wu Q . Gap junctional intercellular communication and endoplasmic reticulum stress regulate chronic cadmium exposure induced apoptosis in HK-2 cells. Toxicol Lett. 2018; 288:35-43. DOI: 10.1016/j.toxlet.2018.02.013. View

17.

Lee H, Oh S . Autophagy-mediated cytoplasmic accumulation of p53 leads to apoptosis through DRAM-BAX in cadmium-exposed human proximal tubular cells. Biochem Biophys Res Commun. 2020; 534:128-133. DOI: 10.1016/j.bbrc.2020.12.019. View

18.

Tonelli C, Chio I, Tuveson D . Transcriptional Regulation by Nrf2. Antioxid Redox Signal. 2017; 29(17):1727-1745. PMC: 6208165. DOI: 10.1089/ars.2017.7342. View

19.

Fang Y, Xiang Y, Lu X, Dong X, Zhang J, Zhong S . Epigenetic dysregulation of Mdr1b in the blood-testis barrier contributes to dyszoospermia in mice exposed to cadmium. Ecotoxicol Environ Saf. 2020; 190:110142. DOI: 10.1016/j.ecoenv.2019.110142. View

20.

Ru W, Zhang X, Yue B, Qi A, Shen X, Huang Y . Insight into mA methylation from occurrence to functions. Open Biol. 2020; 10(9):200091. PMC: 7536083. DOI: 10.1098/rsob.200091. View

21.

Huang W, Chen T, Fang K, Zeng Z, Ye H, Chen Y . N6-methyladenosine methyltransferases: functions, regulation, and clinical potential. J Hematol Oncol. 2021; 14(1):117. PMC: 8313886. DOI: 10.1186/s13045-021-01129-8. View