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PACS-2 deficiency aggravates tubular injury in diabetic kidney disease by inhibiting ER-phagy

Autophagy of endoplasmic reticulum (ER-phagy) selectively removes damaged ER through autophagy-lysosome pathway, acting as an adaptive mechanism to alleviate ER stress and restore ER homeostasis. However, the role and precise mechanism of ER-phagy in tubular injury of diabetic kidney disease (DKD) r...

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Autores principales: Yang, Jinfei, Li, Li, Li, Chenrui, Chen, Wei, Liu, Yan, Luo, Shilu, Zhao, Chanyue, Han, Yachun, Yang, Ming, Zhao, Hao, Jiang, Na, Xi, Yiyun, Tang, Chengyuan, Cai, Juan, Xiao, Li, Liu, Huafeng, Sun, Lin
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10550977/
https://www.ncbi.nlm.nih.gov/pubmed/37794057
http://dx.doi.org/10.1038/s41419-023-06175-3
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author Yang, Jinfei
Li, Li
Li, Chenrui
Chen, Wei
Liu, Yan
Luo, Shilu
Zhao, Chanyue
Han, Yachun
Yang, Ming
Zhao, Hao
Jiang, Na
Xi, Yiyun
Tang, Chengyuan
Cai, Juan
Xiao, Li
Liu, Huafeng
Sun, Lin
author_facet Yang, Jinfei
Li, Li
Li, Chenrui
Chen, Wei
Liu, Yan
Luo, Shilu
Zhao, Chanyue
Han, Yachun
Yang, Ming
Zhao, Hao
Jiang, Na
Xi, Yiyun
Tang, Chengyuan
Cai, Juan
Xiao, Li
Liu, Huafeng
Sun, Lin
author_sort Yang, Jinfei
collection PubMed
description Autophagy of endoplasmic reticulum (ER-phagy) selectively removes damaged ER through autophagy-lysosome pathway, acting as an adaptive mechanism to alleviate ER stress and restore ER homeostasis. However, the role and precise mechanism of ER-phagy in tubular injury of diabetic kidney disease (DKD) remain obscure. In the present study, we demonstrated that ER-phagy of renal tubular cells was severely impaired in streptozocin (STZ)-induced diabetic mice, with a decreased expression of phosphofurin acidic cluster sorting protein 2 (PACS-2), a membrane trafficking protein which was involved in autophagy, and a reduction of family with sequence similarity 134 member B (FAM134B), one ER-phagy receptor. These changes were further aggravated in mice with proximal tubule specific knockout of Pacs-2 gene. In vitro, transfection of HK-2 cells with PACS-2 overexpression plasmid partially improved the impairment of ER-phagy and the reduction of FAM134B, both of which were induced in high glucose ambience; while the effect was blocked by FAM134B siRNA. Mechanistically, PACS-2 interacted with and promoted the nuclear translocation of transcription factor EB (TFEB), which was reported to activate the expression of FAM134B. Collectively, these data unveiled that PACS-2 deficiency aggravates renal tubular injury in DKD via inhibiting ER-phagy through TFEB/FAM134B pathway.
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spelling pubmed-105509772023-10-06 PACS-2 deficiency aggravates tubular injury in diabetic kidney disease by inhibiting ER-phagy Yang, Jinfei Li, Li Li, Chenrui Chen, Wei Liu, Yan Luo, Shilu Zhao, Chanyue Han, Yachun Yang, Ming Zhao, Hao Jiang, Na Xi, Yiyun Tang, Chengyuan Cai, Juan Xiao, Li Liu, Huafeng Sun, Lin Cell Death Dis Article Autophagy of endoplasmic reticulum (ER-phagy) selectively removes damaged ER through autophagy-lysosome pathway, acting as an adaptive mechanism to alleviate ER stress and restore ER homeostasis. However, the role and precise mechanism of ER-phagy in tubular injury of diabetic kidney disease (DKD) remain obscure. In the present study, we demonstrated that ER-phagy of renal tubular cells was severely impaired in streptozocin (STZ)-induced diabetic mice, with a decreased expression of phosphofurin acidic cluster sorting protein 2 (PACS-2), a membrane trafficking protein which was involved in autophagy, and a reduction of family with sequence similarity 134 member B (FAM134B), one ER-phagy receptor. These changes were further aggravated in mice with proximal tubule specific knockout of Pacs-2 gene. In vitro, transfection of HK-2 cells with PACS-2 overexpression plasmid partially improved the impairment of ER-phagy and the reduction of FAM134B, both of which were induced in high glucose ambience; while the effect was blocked by FAM134B siRNA. Mechanistically, PACS-2 interacted with and promoted the nuclear translocation of transcription factor EB (TFEB), which was reported to activate the expression of FAM134B. Collectively, these data unveiled that PACS-2 deficiency aggravates renal tubular injury in DKD via inhibiting ER-phagy through TFEB/FAM134B pathway. Nature Publishing Group UK 2023-10-04 /pmc/articles/PMC10550977/ /pubmed/37794057 http://dx.doi.org/10.1038/s41419-023-06175-3 Text en © The Author(s) 2023 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
Yang, Jinfei
Li, Li
Li, Chenrui
Chen, Wei
Liu, Yan
Luo, Shilu
Zhao, Chanyue
Han, Yachun
Yang, Ming
Zhao, Hao
Jiang, Na
Xi, Yiyun
Tang, Chengyuan
Cai, Juan
Xiao, Li
Liu, Huafeng
Sun, Lin
PACS-2 deficiency aggravates tubular injury in diabetic kidney disease by inhibiting ER-phagy
title PACS-2 deficiency aggravates tubular injury in diabetic kidney disease by inhibiting ER-phagy
title_full PACS-2 deficiency aggravates tubular injury in diabetic kidney disease by inhibiting ER-phagy
title_fullStr PACS-2 deficiency aggravates tubular injury in diabetic kidney disease by inhibiting ER-phagy
title_full_unstemmed PACS-2 deficiency aggravates tubular injury in diabetic kidney disease by inhibiting ER-phagy
title_short PACS-2 deficiency aggravates tubular injury in diabetic kidney disease by inhibiting ER-phagy
title_sort pacs-2 deficiency aggravates tubular injury in diabetic kidney disease by inhibiting er-phagy
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10550977/
https://www.ncbi.nlm.nih.gov/pubmed/37794057
http://dx.doi.org/10.1038/s41419-023-06175-3
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