2. Academic Validation
  3. Dysregulated lipid metabolism is associated with kidney allograft fibrosis

Dysregulated lipid metabolism is associated with kidney allograft fibrosis

  • Lipids Health Dis. 2024 Feb 3;23(1):37. doi: 10.1186/s12944-024-02021-3.
Linjie Peng # 1 2 3,  Chang Wang # 1 2 3,  Shuangjin Yu 1 2 3,  Qihao Li 1 2 3,  Guobin Wu 1 2 3,  Weijie Lai 1 2 3,  Jianliang Min 1 2 3,  Guodong Chen 4 5 6
Affiliations

Affiliations

  • 1 Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China.
  • 2 Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
  • 3 The First Affiliated Hospital, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Sun Yat-sen University, Guangzhou, China.
  • 4 Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China. [email protected].
  • 5 Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China. [email protected].
  • 6 The First Affiliated Hospital, Guangdong Provincial International Cooperation Base of Science and Technology (Organ Transplantation), Sun Yat-sen University, Guangzhou, China. [email protected].
  • # Contributed equally.
PMID: 38308271 DOI: 10.1186/s12944-024-02021-3
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.

Keywords

CPT1A; Fibrosis; IF/TA; Kidney allograft; Lipid metabolism.

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