Rosiglitazone attenuates Acute Kidney Injury from hepatic ischemia-reperfusion in mice by inhibiting arachidonic acid metabolism through the PPAR-γ/NF-κB pathway.
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引用次数: 0
Abstract
Background: Acute Kidney Injury (AKI), a prevalent complication of Liver Transplantation (LT) that occurs during the perioperative period has been established to profoundly impact the prognosis of transplant recipients. This study aimed to investigate the mechanism of the hepatic IRI-induced AKI and to identify potential therapeutic targets for treating this condition and improving the prognosis of LT patients.
Methods: An integrated transcriptomics and proteomics approach was employed to investigate transcriptional and proteomic alterations in hepatic IRI-induced AKI and the hypoxia-reoxygenation (H/R) model using TCMK-1 cells and the hepatic IRI-induced AKI mouse model using male C57BL/6 J mice were employed to elucidate the underlying mechanisms. Hematoxylin-eosin staining, reverse transcription quantitative polymerase chain reaction, enzyme-linked immunosorbent assay and Western blot were used to assess the effect of Rosiglitazone (RGZ) on hepatic IRI-induced AKI in vitro and in vivo.
Results: According to the results, 322 genes and 128 proteins were differentially expressed between the sham and AKI groups. Furthermore, Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomics (KEGG) pathway analyses revealed significant enrichment in pathways related to amino acid and lipid metabolism. Additionally, the Protein-Protein Interaction (PPI) network analysis of the kidney tissues obtained from a hepatic IRI-induced AKI mouse model highlighted arachidonic acid metabolism as the most prominent pathway. Animal and cellular analyses further revealed that RGZ, a PPAR-γ agonist, could inhibit the expression of the PPAR-γ/NF-κB signaling pathway-associated proteins in in vitro and in vivo.
Conclusions: These findings collectively suggest that RGZ ameliorates hepatic IRI-induced AKI via PPAR-γ/NF-κB signaling pathway modulation, highlighting PPAR-γ as a crucial therapeutic target for AKI prevention post-LT.
背景：急性肾损伤（AKI）是肝移植（LT）围手术期的一种常见并发症，已被证实会严重影响移植受者的预后。本研究旨在探究肝脏IRI诱发AKI的机制，并确定治疗这一病症和改善LT患者预后的潜在治疗靶点：方法：采用转录组学和蛋白质组学的综合方法研究肝脏IRI诱导的AKI的转录和蛋白质组学改变，并采用TCMK-1细胞的低氧-复氧（H/R）模型和雄性C57BL/6 J小鼠的肝脏IRI诱导的AKI小鼠模型来阐明其潜在机制。采用血红素-伊红染色、逆转录定量聚合酶链反应、酶联免疫吸附试验和 Western 印迹等方法评估了罗格列酮（RGZ）对肝脏 IRI 诱导的 AKI 的体内外影响：结果显示，假性组和AKI组之间有322个基因和128个蛋白质存在差异表达。此外，基因本体（GO）和京都基因和基因组学百科全书（KEGG）通路分析显示，与氨基酸和脂质代谢相关的通路显著富集。此外，对肝脏 IRI 诱导的 AKI 小鼠模型肾脏组织进行的蛋白质-蛋白质相互作用（PPI）网络分析显示，花生四烯酸代谢是最重要的途径。动物和细胞分析进一步显示，RGZ作为一种PPAR-γ激动剂，可抑制体外和体内PPAR-γ/NF-κB信号通路相关蛋白的表达：这些发现共同表明，RGZ 可通过调节 PPAR-γ/NF-κB 信号通路改善肝 IRI 诱导的 AKI，突出了 PPAR-γ 是预防 LT 后 AKI 的关键治疗靶点。
期刊介绍：
Inflammation Research (IR) publishes peer-reviewed papers on all aspects of inflammation and related fields including histopathology, immunological mechanisms, gene expression, mediators, experimental models, clinical investigations and the effect of drugs. Related fields are broadly defined and include for instance, allergy and asthma, shock, pain, joint damage, skin disease as well as clinical trials of relevant drugs.
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