Cadmium disrupted homeostasis of proximal renal tubular cells via targeting ATF4-CHOP complex into the nucleus
Cadmium, a ubiquitous toxic metal and environmental pollutant, is associated with several renal metabolic disorders and disrupts the homeostasis of kidneys in humans and animals. However, the precise molecular mechanism remains poorly elucidated. The present study investigated the role of the ATF4-C...
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Elsevier
2025-05-01
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| Series: | Poultry Science |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0032579125002986 |
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| author | Muhammad Asmat Ullah Saleem Ying-Xin Zhao Farhat Bano Yi-Xi Tang Mu-Zi Li Kanwar Kumar Malhi Xiao-Wei Li Xue-Nan Li Yi Zhao Jin-Long Li |
| author_facet | Muhammad Asmat Ullah Saleem Ying-Xin Zhao Farhat Bano Yi-Xi Tang Mu-Zi Li Kanwar Kumar Malhi Xiao-Wei Li Xue-Nan Li Yi Zhao Jin-Long Li |
| author_sort | Muhammad Asmat Ullah Saleem |
| collection | DOAJ |
| description | Cadmium, a ubiquitous toxic metal and environmental pollutant, is associated with several renal metabolic disorders and disrupts the homeostasis of kidneys in humans and animals. However, the precise molecular mechanism remains poorly elucidated. The present study investigated the role of the ATF4-CHOP nuclear transcriptional axis and its interactions with cellular pathways in cadmium-induced nephrotoxicity. We acquired 120 one-day-old chickens, randomly divided them into four groups (Con, Cd35, Cd70, Cd140), and were treated with graded cadmium doses for 90 days. The kidney tissues were collected for comprehensive histopathological, biochemical, and molecular analyses using western blotting, qRT-PCR, immunofluorescence, and tunel assay. Subsequently, we revealed that cadmium exposure induced ER stress, significantly upregulated CHOP expression, and activated pro-apoptotic ATF4-CHOP axis. Our findings revealed a complex interplay, where ER stress activated inflammation. Concurrently, mitochondrial disruption elevated ROS production and oxidative stress, which impaired renal homeostasis. Moreover, inhibition of autophagy and mitophagy led to the accumulation of damaged cell organelles, further exacerbating apoptotic signaling. Our results elucidate that an integrated network of cellular stress pathways mediates cadmium-induced renal toxicity, with the ATF4-CHOP axis acting as a crucial pro-apoptotic pathway. This study provides critical insights into the mechanisms of cadmium-induced nephrotoxicity and potential therapeutic interventions to mitigate heavy metal-induced renal homeostasis disruption and renal damage. |
| format | Article |
| id | doaj-art-d721c1c82b674f85b97d7a91b48c6b5f |
| institution | DOAJ |
| issn | 0032-5791 |
| language | English |
| publishDate | 2025-05-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Poultry Science |
| spelling | doaj-art-d721c1c82b674f85b97d7a91b48c6b5f2025-08-20T03:10:21ZengElsevierPoultry Science0032-57912025-05-01104510505910.1016/j.psj.2025.105059Cadmium disrupted homeostasis of proximal renal tubular cells via targeting ATF4-CHOP complex into the nucleusMuhammad Asmat Ullah Saleem0Ying-Xin Zhao1Farhat Bano2Yi-Xi Tang3Mu-Zi Li4Kanwar Kumar Malhi5Xiao-Wei Li6Xue-Nan Li7Yi Zhao8Jin-Long Li9College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR ChinaCollege of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR ChinaCollege of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR ChinaCollege of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR ChinaCollege of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR ChinaCollege of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR ChinaCollege of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR ChinaCollege of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, PR ChinaCollege of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, PR ChinaCollege of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Key Laboratory of the Provincial Education Department of Heilongjiang for Common Animal Disease Prevention and Treatment, Northeast Agricultural University, Harbin, 150030, PR China; Heilongjiang Key Laboratory for Laboratory Animals and Comparative Medicine, Northeast Agricultural University, Harbin, 150030, PR China; Corresponding author at: College of Veterinary Medicine, Northeast Agricultural University, Harbin, 150030, PR China.Cadmium, a ubiquitous toxic metal and environmental pollutant, is associated with several renal metabolic disorders and disrupts the homeostasis of kidneys in humans and animals. However, the precise molecular mechanism remains poorly elucidated. The present study investigated the role of the ATF4-CHOP nuclear transcriptional axis and its interactions with cellular pathways in cadmium-induced nephrotoxicity. We acquired 120 one-day-old chickens, randomly divided them into four groups (Con, Cd35, Cd70, Cd140), and were treated with graded cadmium doses for 90 days. The kidney tissues were collected for comprehensive histopathological, biochemical, and molecular analyses using western blotting, qRT-PCR, immunofluorescence, and tunel assay. Subsequently, we revealed that cadmium exposure induced ER stress, significantly upregulated CHOP expression, and activated pro-apoptotic ATF4-CHOP axis. Our findings revealed a complex interplay, where ER stress activated inflammation. Concurrently, mitochondrial disruption elevated ROS production and oxidative stress, which impaired renal homeostasis. Moreover, inhibition of autophagy and mitophagy led to the accumulation of damaged cell organelles, further exacerbating apoptotic signaling. Our results elucidate that an integrated network of cellular stress pathways mediates cadmium-induced renal toxicity, with the ATF4-CHOP axis acting as a crucial pro-apoptotic pathway. This study provides critical insights into the mechanisms of cadmium-induced nephrotoxicity and potential therapeutic interventions to mitigate heavy metal-induced renal homeostasis disruption and renal damage.http://www.sciencedirect.com/science/article/pii/S0032579125002986CadmiumKidneyHomeostasisNephrotoxicityATF4-CHOP axis |
| spellingShingle | Muhammad Asmat Ullah Saleem Ying-Xin Zhao Farhat Bano Yi-Xi Tang Mu-Zi Li Kanwar Kumar Malhi Xiao-Wei Li Xue-Nan Li Yi Zhao Jin-Long Li Cadmium disrupted homeostasis of proximal renal tubular cells via targeting ATF4-CHOP complex into the nucleus Poultry Science Cadmium Kidney Homeostasis Nephrotoxicity ATF4-CHOP axis |
| title | Cadmium disrupted homeostasis of proximal renal tubular cells via targeting ATF4-CHOP complex into the nucleus |
| title_full | Cadmium disrupted homeostasis of proximal renal tubular cells via targeting ATF4-CHOP complex into the nucleus |
| title_fullStr | Cadmium disrupted homeostasis of proximal renal tubular cells via targeting ATF4-CHOP complex into the nucleus |
| title_full_unstemmed | Cadmium disrupted homeostasis of proximal renal tubular cells via targeting ATF4-CHOP complex into the nucleus |
| title_short | Cadmium disrupted homeostasis of proximal renal tubular cells via targeting ATF4-CHOP complex into the nucleus |
| title_sort | cadmium disrupted homeostasis of proximal renal tubular cells via targeting atf4 chop complex into the nucleus |
| topic | Cadmium Kidney Homeostasis Nephrotoxicity ATF4-CHOP axis |
| url | http://www.sciencedirect.com/science/article/pii/S0032579125002986 |
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