Dysregulated lipid metabolism is associated with kidney allograft fibrosis
Abstract Background Interstitial fibrosis and tubular atrophy (IF/TA), a histologic feature of kidney allograft destruction, is linked to decreased allograft survival. The role of lipid metabolism is well-acknowledged in the area of chronic kidney diseases; however, its role in kidney allograft fibr...
| Main Authors: | , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMC
2024-02-01
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| Series: | Lipids in Health and Disease |
| Subjects: | |
| Online Access: | https://doi.org/10.1186/s12944-024-02021-3 |
| _version_ | 1797273397262024704 |
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| author | Linjie Peng Chang Wang Shuangjin Yu Qihao Li Guobin Wu Weijie Lai Jianliang Min Guodong Chen |
| author_facet | Linjie Peng Chang Wang Shuangjin Yu Qihao Li Guobin Wu Weijie Lai Jianliang Min Guodong Chen |
| author_sort | Linjie Peng |
| collection | DOAJ |
| description | Abstract Background Interstitial fibrosis and tubular atrophy (IF/TA), a histologic feature of kidney allograft destruction, is linked to decreased allograft survival. The role of lipid metabolism is well-acknowledged in the area of chronic kidney diseases; however, its role in kidney allograft fibrosis is still unclarified. In this study, how lipid metabolism contributes to kidney allografts fibrosis was examined. Methods A comprehensive bioinformatic comparison between IF/TA and normal kidney allograft in the Gene Expression Omnibus (GEO) database was conducted. Further validations through transcriptome profiling or pathological staining of human recipient biopsy samples and in rat models of kidney transplantation were performed. Additionally, the effects of enhanced lipid metabolism on changes in the fibrotic phenotype induced by TGF-β1 were examined in HK-2 cell. Results In-depth analysis of the GEO dataset revealed a notable downregulation of lipid metabolism pathways in human kidney allografts with IF/TA. This decrease was associated with increased level of allograft rejection, inflammatory responses, and epithelial mesenchymal transition (EMT). Pathway enrichment analysis showed the downregulation in mitochondrial LC-fatty acid beta-oxidation, fatty acid beta-oxidation (FAO), and fatty acid biosynthesis. Dysregulated fatty acid metabolism was also observed in biopsy samples from human kidney transplants and in fibrotic rat kidney allografts. Notably, the areas affected by IF/TA had increased immune cell infiltration, during which increased EMT biomarkers and reduced CPT1A expression, a key FAO enzyme, were shown by immunohistochemistry. Moreover, under TGF-β1 induction, activating CPT1A with the compound C75 effectively inhibited migration and EMT process in HK-2 cells. Conclusions This study reveal a critical correlation between dysregulated lipid metabolism and kidney allograft fibrosis. Enhancing lipid metabolism with CPT1A agonists could be a therapeutic approach to mitigate kidney allografts fibrosis. |
| first_indexed | 2024-03-07T14:43:47Z |
| format | Article |
| id | doaj.art-8662e3f159404671aca4c977b9ead529 |
| institution | Directory Open Access Journal |
| issn | 1476-511X |
| language | English |
| last_indexed | 2024-03-07T14:43:47Z |
| publishDate | 2024-02-01 |
| publisher | BMC |
| record_format | Article |
| series | Lipids in Health and Disease |
| spelling | doaj.art-8662e3f159404671aca4c977b9ead5292024-03-05T20:07:53ZengBMCLipids in Health and Disease1476-511X2024-02-0123111410.1186/s12944-024-02021-3Dysregulated lipid metabolism is associated with kidney allograft fibrosisLinjie Peng0Chang Wang1Shuangjin Yu2Qihao Li3Guobin Wu4Weijie Lai5Jianliang Min6Guodong Chen7Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen UniversityOrgan Transplant Center, The First Affiliated Hospital, Sun Yat-sen UniversityOrgan Transplant Center, The First Affiliated Hospital, Sun Yat-sen UniversityOrgan Transplant Center, The First Affiliated Hospital, Sun Yat-sen UniversityOrgan Transplant Center, The First Affiliated Hospital, Sun Yat-sen UniversityOrgan Transplant Center, The First Affiliated Hospital, Sun Yat-sen UniversityOrgan Transplant Center, The First Affiliated Hospital, Sun Yat-sen UniversityOrgan Transplant Center, The First Affiliated Hospital, Sun Yat-sen UniversityAbstract Background Interstitial fibrosis and tubular atrophy (IF/TA), a histologic feature of kidney allograft destruction, is linked to decreased allograft survival. The role of lipid metabolism is well-acknowledged in the area of chronic kidney diseases; however, its role in kidney allograft fibrosis is still unclarified. In this study, how lipid metabolism contributes to kidney allografts fibrosis was examined. Methods A comprehensive bioinformatic comparison between IF/TA and normal kidney allograft in the Gene Expression Omnibus (GEO) database was conducted. Further validations through transcriptome profiling or pathological staining of human recipient biopsy samples and in rat models of kidney transplantation were performed. Additionally, the effects of enhanced lipid metabolism on changes in the fibrotic phenotype induced by TGF-β1 were examined in HK-2 cell. Results In-depth analysis of the GEO dataset revealed a notable downregulation of lipid metabolism pathways in human kidney allografts with IF/TA. This decrease was associated with increased level of allograft rejection, inflammatory responses, and epithelial mesenchymal transition (EMT). Pathway enrichment analysis showed the downregulation in mitochondrial LC-fatty acid beta-oxidation, fatty acid beta-oxidation (FAO), and fatty acid biosynthesis. Dysregulated fatty acid metabolism was also observed in biopsy samples from human kidney transplants and in fibrotic rat kidney allografts. Notably, the areas affected by IF/TA had increased immune cell infiltration, during which increased EMT biomarkers and reduced CPT1A expression, a key FAO enzyme, were shown by immunohistochemistry. Moreover, under TGF-β1 induction, activating CPT1A with the compound C75 effectively inhibited migration and EMT process in HK-2 cells. Conclusions This study reveal a critical correlation between dysregulated lipid metabolism and kidney allograft fibrosis. Enhancing lipid metabolism with CPT1A agonists could be a therapeutic approach to mitigate kidney allografts fibrosis.https://doi.org/10.1186/s12944-024-02021-3Lipid metabolismCPT1AKidney allograftFibrosisIF/TA |
| spellingShingle | Linjie Peng Chang Wang Shuangjin Yu Qihao Li Guobin Wu Weijie Lai Jianliang Min Guodong Chen Dysregulated lipid metabolism is associated with kidney allograft fibrosis Lipids in Health and Disease Lipid metabolism CPT1A Kidney allograft Fibrosis IF/TA |
| title | Dysregulated lipid metabolism is associated with kidney allograft fibrosis |
| title_full | Dysregulated lipid metabolism is associated with kidney allograft fibrosis |
| title_fullStr | Dysregulated lipid metabolism is associated with kidney allograft fibrosis |
| title_full_unstemmed | Dysregulated lipid metabolism is associated with kidney allograft fibrosis |
| title_short | Dysregulated lipid metabolism is associated with kidney allograft fibrosis |
| title_sort | dysregulated lipid metabolism is associated with kidney allograft fibrosis |
| topic | Lipid metabolism CPT1A Kidney allograft Fibrosis IF/TA |
| url | https://doi.org/10.1186/s12944-024-02021-3 |
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