Cargando…
PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease
BACKGROUND: Lipid accumulation in tubular cells plays a key role in diabetic kidney disease (DKD). Targeting lipid metabolism disorders has clinical value in delaying the progression of DKD, but the precise mechanism by which molecules mediate lipid-related kidney injury remains unclear. Phosphofuri...
Autores principales: | , , , , , , , , , , , , , , |
---|---|
Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2022
|
Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9502582/ https://www.ncbi.nlm.nih.gov/pubmed/36138342 http://dx.doi.org/10.1186/s10020-022-00545-x |
_version_ | 1784795741941661696 |
---|---|
author | Zhao, Chanyue Li, Li Li, Chenrui Tang, Chengyuan Cai, Juan Liu, Yu Yang, Jinfei Xi, Yiyun Yang, Ming Jiang, Na Han, Yachun Liu, Yan Luo, Shilu Xiao, Li Sun, Lin |
author_facet | Zhao, Chanyue Li, Li Li, Chenrui Tang, Chengyuan Cai, Juan Liu, Yu Yang, Jinfei Xi, Yiyun Yang, Ming Jiang, Na Han, Yachun Liu, Yan Luo, Shilu Xiao, Li Sun, Lin |
author_sort | Zhao, Chanyue |
collection | PubMed |
description | BACKGROUND: Lipid accumulation in tubular cells plays a key role in diabetic kidney disease (DKD). Targeting lipid metabolism disorders has clinical value in delaying the progression of DKD, but the precise mechanism by which molecules mediate lipid-related kidney injury remains unclear. Phosphofurin acidic cluster sorting protein 2 (PACS-2) is a multifunctional sorting protein that plays a role in lipid metabolism. This study determined the role of PACS-2 in lipid-related kidney injury in DKD. METHODS: Diabetes was induced by a high-fat diet combined with intraperitoneal injections of streptozotocin (HFD/STZ) in proximal tubule-specific knockout of Pacs-2 mice (PT-Pacs-2(−/−) mice) and the control mice (Pacs-2(fl/fl) mice). Transcriptomic analysis was performed between Pacs-2(fl/fl) mice and PT-Pacs-2(−/−) mice. RESULTS: Diabetic PT-Pacs-2(−/−) mice developed more severe tubule injury and proteinuria compared to diabetic Pacs-2(fl/fl) mice, which accompanied with increasing lipid synthesis, uptake and decreasing cholesterol efflux as well as lipid accumulation in tubules of the kidney. Furthermore, transcriptome analysis showed that the mRNA level of sterol O-acyltransferase 1 (Soat1) was up-regulated in the kidney of control PT-Pacs-2(−/−) mice. Transfection of HK2 cells with PACS-2 siRNA under high glucose plus palmitic acid (HGPA) condition aggravated lipid deposition and increased the expression of SOAT1 and sterol regulatory element-binding proteins (SREBPs), while the effect was blocked partially in that of co-transfection of SOAT1 siRNA. CONCLUSIONS: PACS-2 has a protective role against lipid-related kidney injury in DKD through SOAT1/SREBPs signaling. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-022-00545-x. |
format | Online Article Text |
id | pubmed-9502582 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-95025822022-09-24 PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease Zhao, Chanyue Li, Li Li, Chenrui Tang, Chengyuan Cai, Juan Liu, Yu Yang, Jinfei Xi, Yiyun Yang, Ming Jiang, Na Han, Yachun Liu, Yan Luo, Shilu Xiao, Li Sun, Lin Mol Med Research Article BACKGROUND: Lipid accumulation in tubular cells plays a key role in diabetic kidney disease (DKD). Targeting lipid metabolism disorders has clinical value in delaying the progression of DKD, but the precise mechanism by which molecules mediate lipid-related kidney injury remains unclear. Phosphofurin acidic cluster sorting protein 2 (PACS-2) is a multifunctional sorting protein that plays a role in lipid metabolism. This study determined the role of PACS-2 in lipid-related kidney injury in DKD. METHODS: Diabetes was induced by a high-fat diet combined with intraperitoneal injections of streptozotocin (HFD/STZ) in proximal tubule-specific knockout of Pacs-2 mice (PT-Pacs-2(−/−) mice) and the control mice (Pacs-2(fl/fl) mice). Transcriptomic analysis was performed between Pacs-2(fl/fl) mice and PT-Pacs-2(−/−) mice. RESULTS: Diabetic PT-Pacs-2(−/−) mice developed more severe tubule injury and proteinuria compared to diabetic Pacs-2(fl/fl) mice, which accompanied with increasing lipid synthesis, uptake and decreasing cholesterol efflux as well as lipid accumulation in tubules of the kidney. Furthermore, transcriptome analysis showed that the mRNA level of sterol O-acyltransferase 1 (Soat1) was up-regulated in the kidney of control PT-Pacs-2(−/−) mice. Transfection of HK2 cells with PACS-2 siRNA under high glucose plus palmitic acid (HGPA) condition aggravated lipid deposition and increased the expression of SOAT1 and sterol regulatory element-binding proteins (SREBPs), while the effect was blocked partially in that of co-transfection of SOAT1 siRNA. CONCLUSIONS: PACS-2 has a protective role against lipid-related kidney injury in DKD through SOAT1/SREBPs signaling. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1186/s10020-022-00545-x. BioMed Central 2022-09-23 /pmc/articles/PMC9502582/ /pubmed/36138342 http://dx.doi.org/10.1186/s10020-022-00545-x Text en © The Author(s) 2022 https://creativecommons.org/licenses/by/4.0/Open AccessThis 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 licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence 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 licence, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) . |
spellingShingle | Research Article Zhao, Chanyue Li, Li Li, Chenrui Tang, Chengyuan Cai, Juan Liu, Yu Yang, Jinfei Xi, Yiyun Yang, Ming Jiang, Na Han, Yachun Liu, Yan Luo, Shilu Xiao, Li Sun, Lin PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease |
title | PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease |
title_full | PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease |
title_fullStr | PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease |
title_full_unstemmed | PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease |
title_short | PACS-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease |
title_sort | pacs-2 deficiency in tubular cells aggravates lipid-related kidney injury in diabetic kidney disease |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9502582/ https://www.ncbi.nlm.nih.gov/pubmed/36138342 http://dx.doi.org/10.1186/s10020-022-00545-x |
work_keys_str_mv | AT zhaochanyue pacs2deficiencyintubularcellsaggravateslipidrelatedkidneyinjuryindiabetickidneydisease AT lili pacs2deficiencyintubularcellsaggravateslipidrelatedkidneyinjuryindiabetickidneydisease AT lichenrui pacs2deficiencyintubularcellsaggravateslipidrelatedkidneyinjuryindiabetickidneydisease AT tangchengyuan pacs2deficiencyintubularcellsaggravateslipidrelatedkidneyinjuryindiabetickidneydisease AT caijuan pacs2deficiencyintubularcellsaggravateslipidrelatedkidneyinjuryindiabetickidneydisease AT liuyu pacs2deficiencyintubularcellsaggravateslipidrelatedkidneyinjuryindiabetickidneydisease AT yangjinfei pacs2deficiencyintubularcellsaggravateslipidrelatedkidneyinjuryindiabetickidneydisease AT xiyiyun pacs2deficiencyintubularcellsaggravateslipidrelatedkidneyinjuryindiabetickidneydisease AT yangming pacs2deficiencyintubularcellsaggravateslipidrelatedkidneyinjuryindiabetickidneydisease AT jiangna pacs2deficiencyintubularcellsaggravateslipidrelatedkidneyinjuryindiabetickidneydisease AT hanyachun pacs2deficiencyintubularcellsaggravateslipidrelatedkidneyinjuryindiabetickidneydisease AT liuyan pacs2deficiencyintubularcellsaggravateslipidrelatedkidneyinjuryindiabetickidneydisease AT luoshilu pacs2deficiencyintubularcellsaggravateslipidrelatedkidneyinjuryindiabetickidneydisease AT xiaoli pacs2deficiencyintubularcellsaggravateslipidrelatedkidneyinjuryindiabetickidneydisease AT sunlin pacs2deficiencyintubularcellsaggravateslipidrelatedkidneyinjuryindiabetickidneydisease |