HO-1 activation contributes to cadmium-induced ferroptosis in renal tubular epithelial cells via increasing the labile iron pool and promoting mitochondrial ROS generation
Cadmium (Cd), a prevalent environmental contaminant, has attracted widespread attention due to its serious health hazards. Ferroptosis is a form of iron-dependent oxidative cell death that contributes to the development of various kidney diseases. However, the mechanisms underlying the occurrence of...
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| Veröffentlicht in: | Chemico-biological interactions 2024-08, Vol.399, p.111152, Article 111152 |
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| creator | Lv, Yan-Ting Liu, Tian-Bin Li, Yue Wang, Zhen-Yong Lian, Cai-Yu Wang, Lin |
| description | Cadmium (Cd), a prevalent environmental contaminant, has attracted widespread attention due to its serious health hazards. Ferroptosis is a form of iron-dependent oxidative cell death that contributes to the development of various kidney diseases. However, the mechanisms underlying the occurrence of ferroptosis in Cd-induced renal tubular epithelial cells (TECs) have not been fully elucidated. Hereby, both in-vitro and in-vivo experiments were established to elucidate this issue. In this study, we found that Cd elicited accumulation of lipid peroxides due to intracellular ferrous ion (Fe2+) overload and glutathione depletion, contributing to ferroptosis. Inhibition of ferroptosis via chelation of Fe2+ or reduction of lipid peroxidation can significantly mitigate Cd-induced cytotoxicity. Renal transcriptome analysis revealed that the activation of heme oxygenase 1 (HO-1) was closely related to ferroptosis in Cd-induced TECs injury. Cd-induced ferroptosis and resultant TECs injury are significantly alleviated due to HO-1 inhibition, demonstrating the crucial role of HO-1 in Cd-triggered ferroptosis. Further studies showed that accumulation of lipid peroxides due to iron overload and mitochondrial ROS (mtROS) generation was responsible for HO-1-triggered ferroptosis in Cd-induced cytotoxicity. In conclusion, the current study demonstrates that excessively upregulating HO-1 promotes iron overload and mtROS overproduction to trigger ferroptosis in Cd-induced TECs injury, highlighting that targeting HO-1-mediated ferroptosis may provide new ideas for preventing Cd-induced nephrotoxicity.
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•Cadmium (Cd)-triggered ferroptosis contributes to renal tubule epithelial cells (TECs) injury.•HO-1 hyperactivation is responsible for Cd-induced ferroptosis in renal TECs.•Iron overload and mtROS accumulation due to HO-1 hyperactivation result in Cd-evoked ferroptosis. |
| doi_str_mv | 10.1016/j.cbi.2024.111152 |
| format | Article |
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[Display omitted]
•Cadmium (Cd)-triggered ferroptosis contributes to renal tubule epithelial cells (TECs) injury.•HO-1 hyperactivation is responsible for Cd-induced ferroptosis in renal TECs.•Iron overload and mtROS accumulation due to HO-1 hyperactivation result in Cd-evoked ferroptosis.</description><identifier>ISSN: 0009-2797</identifier><identifier>ISSN: 1872-7786</identifier><identifier>EISSN: 1872-7786</identifier><identifier>DOI: 10.1016/j.cbi.2024.111152</identifier><identifier>PMID: 39025289</identifier><language>eng</language><publisher>Ireland: Elsevier B.V</publisher><subject>Animals ; Cadmium ; Cadmium - toxicity ; Cell Line ; Epithelial Cells - drug effects ; Epithelial Cells - metabolism ; Epithelial Cells - pathology ; Ferroptosis ; Ferroptosis - drug effects ; Glutathione - metabolism ; Heme Oxygenase-1 - metabolism ; HO-1 ; Humans ; Iron - metabolism ; Kidney Tubules - cytology ; Kidney Tubules - drug effects ; Kidney Tubules - metabolism ; Kidney Tubules - pathology ; Lipid peroxidation ; Lipid Peroxidation - drug effects ; Male ; Mice ; Mice, Inbred C57BL ; Mitochondria - drug effects ; Mitochondria - metabolism ; Reactive Oxygen Species - metabolism ; Renal tubule epithelial cell</subject><ispartof>Chemico-biological interactions, 2024-08, Vol.399, p.111152, Article 111152</ispartof><rights>2024 Elsevier B.V.</rights><rights>Copyright © 2024 Elsevier B.V. All rights reserved.</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><cites>FETCH-LOGICAL-c235t-1af78d0eb035e6a5ed4ce2d10ee7e91e735d524d373bb54316a9b74e972682243</cites><orcidid>0000-0001-6531-1748</orcidid></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><linktohtml>$$Uhttps://dx.doi.org/10.1016/j.cbi.2024.111152$$EHTML$$P50$$Gelsevier$$H</linktohtml><link.rule.ids>314,780,784,3550,27924,27925,45995</link.rule.ids><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/39025289$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Lv, Yan-Ting</creatorcontrib><creatorcontrib>Liu, Tian-Bin</creatorcontrib><creatorcontrib>Li, Yue</creatorcontrib><creatorcontrib>Wang, Zhen-Yong</creatorcontrib><creatorcontrib>Lian, Cai-Yu</creatorcontrib><creatorcontrib>Wang, Lin</creatorcontrib><title>HO-1 activation contributes to cadmium-induced ferroptosis in renal tubular epithelial cells via increasing the labile iron pool and promoting mitochondrial ROS generation</title><title>Chemico-biological interactions</title><addtitle>Chem Biol Interact</addtitle><description>Cadmium (Cd), a prevalent environmental contaminant, has attracted widespread attention due to its serious health hazards. Ferroptosis is a form of iron-dependent oxidative cell death that contributes to the development of various kidney diseases. However, the mechanisms underlying the occurrence of ferroptosis in Cd-induced renal tubular epithelial cells (TECs) have not been fully elucidated. Hereby, both in-vitro and in-vivo experiments were established to elucidate this issue. In this study, we found that Cd elicited accumulation of lipid peroxides due to intracellular ferrous ion (Fe2+) overload and glutathione depletion, contributing to ferroptosis. Inhibition of ferroptosis via chelation of Fe2+ or reduction of lipid peroxidation can significantly mitigate Cd-induced cytotoxicity. Renal transcriptome analysis revealed that the activation of heme oxygenase 1 (HO-1) was closely related to ferroptosis in Cd-induced TECs injury. Cd-induced ferroptosis and resultant TECs injury are significantly alleviated due to HO-1 inhibition, demonstrating the crucial role of HO-1 in Cd-triggered ferroptosis. Further studies showed that accumulation of lipid peroxides due to iron overload and mitochondrial ROS (mtROS) generation was responsible for HO-1-triggered ferroptosis in Cd-induced cytotoxicity. In conclusion, the current study demonstrates that excessively upregulating HO-1 promotes iron overload and mtROS overproduction to trigger ferroptosis in Cd-induced TECs injury, highlighting that targeting HO-1-mediated ferroptosis may provide new ideas for preventing Cd-induced nephrotoxicity.
[Display omitted]
•Cadmium (Cd)-triggered ferroptosis contributes to renal tubule epithelial cells (TECs) injury.•HO-1 hyperactivation is responsible for Cd-induced ferroptosis in renal TECs.•Iron overload and mtROS accumulation due to HO-1 hyperactivation result in Cd-evoked ferroptosis.</description><subject>Animals</subject><subject>Cadmium</subject><subject>Cadmium - toxicity</subject><subject>Cell Line</subject><subject>Epithelial Cells - drug effects</subject><subject>Epithelial Cells - metabolism</subject><subject>Epithelial Cells - pathology</subject><subject>Ferroptosis</subject><subject>Ferroptosis - drug effects</subject><subject>Glutathione - metabolism</subject><subject>Heme Oxygenase-1 - metabolism</subject><subject>HO-1</subject><subject>Humans</subject><subject>Iron - metabolism</subject><subject>Kidney Tubules - cytology</subject><subject>Kidney Tubules - drug effects</subject><subject>Kidney Tubules - metabolism</subject><subject>Kidney Tubules - pathology</subject><subject>Lipid peroxidation</subject><subject>Lipid Peroxidation - drug effects</subject><subject>Male</subject><subject>Mice</subject><subject>Mice, Inbred C57BL</subject><subject>Mitochondria - drug effects</subject><subject>Mitochondria - metabolism</subject><subject>Reactive Oxygen Species - metabolism</subject><subject>Renal tubule epithelial cell</subject><issn>0009-2797</issn><issn>1872-7786</issn><issn>1872-7786</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2024</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNp9kctuHCEQRVGUKB47-YBsIpbZ9AToB93KKrL8kiyNlMca0VBj14iGDtAj5Zvyk6Y9TpZhU4I6damqS8gHzrac8e7zYWtG3Aommi0vpxWvyIb3UlRS9t1rsmGMDZWQgzwj5ykdyrWg7C05qwcmWtEPG_Lndldxqk3Go84YPDXB54jjkiHRHKjRdsJlqtDbxYCle4gxzDkkTBQ9jeC1o3kZF6cjhRnzIzgsTwacS_SIulAmgk7oH2hJUqdHdEAxlr_mEBzV3tI5hinkFZkwB_MYvI2ryrfdd_oAHuJzb-_Im712Cd6_xAvy8_rqx-Vtdb-7ubv8el8ZUbe54nove8tgZHULnW7BNgaE5QxAwsBB1q1tRWNrWY9j29S808MoGxik6HohmvqCfDrplrZ-LZCymjCtA2kPYUmqZr3oyloZKyg_oSaGlCLs1Rxx0vG34kytHqmDKh6p1SN18qjUfHyRX8YJ7L-Kv6YU4MsJgDLkESGqZBB8WT9GMFnZgP-RfwJJDKVP</recordid><startdate>20240825</startdate><enddate>20240825</enddate><creator>Lv, Yan-Ting</creator><creator>Liu, Tian-Bin</creator><creator>Li, Yue</creator><creator>Wang, Zhen-Yong</creator><creator>Lian, Cai-Yu</creator><creator>Wang, Lin</creator><general>Elsevier B.V</general><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7X8</scope><orcidid>https://orcid.org/0000-0001-6531-1748</orcidid></search><sort><creationdate>20240825</creationdate><title>HO-1 activation contributes to cadmium-induced ferroptosis in renal tubular epithelial cells via increasing the labile iron pool and promoting mitochondrial ROS generation</title><author>Lv, Yan-Ting ; Liu, Tian-Bin ; Li, Yue ; Wang, Zhen-Yong ; Lian, Cai-Yu ; Wang, Lin</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c235t-1af78d0eb035e6a5ed4ce2d10ee7e91e735d524d373bb54316a9b74e972682243</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2024</creationdate><topic>Animals</topic><topic>Cadmium</topic><topic>Cadmium - toxicity</topic><topic>Cell Line</topic><topic>Epithelial Cells - drug effects</topic><topic>Epithelial Cells - metabolism</topic><topic>Epithelial Cells - pathology</topic><topic>Ferroptosis</topic><topic>Ferroptosis - drug effects</topic><topic>Glutathione - metabolism</topic><topic>Heme Oxygenase-1 - metabolism</topic><topic>HO-1</topic><topic>Humans</topic><topic>Iron - metabolism</topic><topic>Kidney Tubules - cytology</topic><topic>Kidney Tubules - drug effects</topic><topic>Kidney Tubules - metabolism</topic><topic>Kidney Tubules - pathology</topic><topic>Lipid peroxidation</topic><topic>Lipid Peroxidation - drug effects</topic><topic>Male</topic><topic>Mice</topic><topic>Mice, Inbred C57BL</topic><topic>Mitochondria - drug effects</topic><topic>Mitochondria - metabolism</topic><topic>Reactive Oxygen Species - metabolism</topic><topic>Renal tubule epithelial cell</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Lv, Yan-Ting</creatorcontrib><creatorcontrib>Liu, Tian-Bin</creatorcontrib><creatorcontrib>Li, Yue</creatorcontrib><creatorcontrib>Wang, Zhen-Yong</creatorcontrib><creatorcontrib>Lian, Cai-Yu</creatorcontrib><creatorcontrib>Wang, Lin</creatorcontrib><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>MEDLINE - Academic</collection><jtitle>Chemico-biological interactions</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Lv, Yan-Ting</au><au>Liu, Tian-Bin</au><au>Li, Yue</au><au>Wang, Zhen-Yong</au><au>Lian, Cai-Yu</au><au>Wang, Lin</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>HO-1 activation contributes to cadmium-induced ferroptosis in renal tubular epithelial cells via increasing the labile iron pool and promoting mitochondrial ROS generation</atitle><jtitle>Chemico-biological interactions</jtitle><addtitle>Chem Biol Interact</addtitle><date>2024-08-25</date><risdate>2024</risdate><volume>399</volume><spage>111152</spage><pages>111152-</pages><artnum>111152</artnum><issn>0009-2797</issn><issn>1872-7786</issn><eissn>1872-7786</eissn><abstract>Cadmium (Cd), a prevalent environmental contaminant, has attracted widespread attention due to its serious health hazards. Ferroptosis is a form of iron-dependent oxidative cell death that contributes to the development of various kidney diseases. However, the mechanisms underlying the occurrence of ferroptosis in Cd-induced renal tubular epithelial cells (TECs) have not been fully elucidated. Hereby, both in-vitro and in-vivo experiments were established to elucidate this issue. In this study, we found that Cd elicited accumulation of lipid peroxides due to intracellular ferrous ion (Fe2+) overload and glutathione depletion, contributing to ferroptosis. Inhibition of ferroptosis via chelation of Fe2+ or reduction of lipid peroxidation can significantly mitigate Cd-induced cytotoxicity. Renal transcriptome analysis revealed that the activation of heme oxygenase 1 (HO-1) was closely related to ferroptosis in Cd-induced TECs injury. Cd-induced ferroptosis and resultant TECs injury are significantly alleviated due to HO-1 inhibition, demonstrating the crucial role of HO-1 in Cd-triggered ferroptosis. Further studies showed that accumulation of lipid peroxides due to iron overload and mitochondrial ROS (mtROS) generation was responsible for HO-1-triggered ferroptosis in Cd-induced cytotoxicity. In conclusion, the current study demonstrates that excessively upregulating HO-1 promotes iron overload and mtROS overproduction to trigger ferroptosis in Cd-induced TECs injury, highlighting that targeting HO-1-mediated ferroptosis may provide new ideas for preventing Cd-induced nephrotoxicity.
[Display omitted]
•Cadmium (Cd)-triggered ferroptosis contributes to renal tubule epithelial cells (TECs) injury.•HO-1 hyperactivation is responsible for Cd-induced ferroptosis in renal TECs.•Iron overload and mtROS accumulation due to HO-1 hyperactivation result in Cd-evoked ferroptosis.</abstract><cop>Ireland</cop><pub>Elsevier B.V</pub><pmid>39025289</pmid><doi>10.1016/j.cbi.2024.111152</doi><orcidid>https://orcid.org/0000-0001-6531-1748</orcidid></addata></record> |
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| subjects | Animals Cadmium Cadmium - toxicity Cell Line Epithelial Cells - drug effects Epithelial Cells - metabolism Epithelial Cells - pathology Ferroptosis Ferroptosis - drug effects Glutathione - metabolism Heme Oxygenase-1 - metabolism HO-1 Humans Iron - metabolism Kidney Tubules - cytology Kidney Tubules - drug effects Kidney Tubules - metabolism Kidney Tubules - pathology Lipid peroxidation Lipid Peroxidation - drug effects Male Mice Mice, Inbred C57BL Mitochondria - drug effects Mitochondria - metabolism Reactive Oxygen Species - metabolism Renal tubule epithelial cell |
| title | HO-1 activation contributes to cadmium-induced ferroptosis in renal tubular epithelial cells via increasing the labile iron pool and promoting mitochondrial ROS generation |
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