脂质代谢失调与肾移植纤维化有关。
Dysregulated lipid metabolism is associated with kidney allograft fibrosis.
机构信息
Organ Transplant Center, The First Affiliated Hospital, Sun Yat-sen University, 58 Zhongshan 2nd Road, Guangzhou, 510080, China.
Guangdong Provincial Key Laboratory of Organ Donation and Transplant Immunology, The First Affiliated Hospital, Sun Yat-sen University, Guangzhou, China.
出版信息
Lipids Health Dis. 2024 Feb 3;23(1):37. doi: 10.1186/s12944-024-02021-3.
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.
背景
间质纤维化和肾小管萎缩（IF/TA）是肾移植损伤的组织学特征，与移植物存活率降低有关。脂质代谢在慢性肾脏病领域的作用得到了广泛认可；然而，其在肾移植纤维化中的作用仍不清楚。在这项研究中，研究了脂质代谢如何导致肾移植纤维化。
方法
在基因表达综合数据库（GEO）中对 IF/TA 与正常肾移植进行了全面的生物信息学比较。通过对人类受者活检样本和大鼠肾移植模型的转录组谱分析或病理染色进行了进一步验证。此外，还研究了增强脂质代谢对 TGF-β1 诱导的纤维化表型变化的影响在 HK-2 细胞中。
结果
对 GEO 数据集的深入分析显示，人类肾移植 IF/TA 中脂质代谢途径明显下调。这种减少与移植物排斥反应、炎症反应和上皮间质转化（EMT）水平的增加有关。通路富集分析显示，线粒体 LC-脂肪酸β氧化、脂肪酸β氧化（FAO）和脂肪酸生物合成下调。在人类肾移植活检样本和纤维化大鼠肾移植中也观察到脂肪酸代谢失调。值得注意的是，IF/TA 受影响的区域免疫细胞浸润增加，免疫组化显示 EMT 标志物增加，关键 FAO 酶 CPT1A 表达减少。此外，在 TGF-β1 诱导下，用化合物 C75 激活 CPT1A 可有效抑制 HK-2 细胞的迁移和 EMT 过程。
结论
本研究揭示了脂质代谢失调与肾移植纤维化之间的重要相关性。用 CPT1A 激动剂增强脂质代谢可能是减轻肾移植纤维化的一种治疗方法。
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