Department of Rheumatology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Department of Nephrology, The Second Affiliated Hospital of Zhejiang University School of Medicine, Hangzhou, China.
Front Immunol. 2023 Jul 31;14:1171318. doi: 10.3389/fimmu.2023.1171318. eCollection 2023.
Dysregulation of cell death and defective clearance of dying cells are closely related to the pathogenesis of lupus nephritis (LN). However, the contribution of a recently discovered form of programmed cell death (PCD) called ferroptosis to LN has not been explored in detail. The purpose of this study was to investigate the role of ferroptosis and its associated metabolic pathways in the pathogenesis of LN.
The composite gene expression scores were calculated by averaging the z-scored transformed log2 expressed genes within each form of PCD and pathway. Immunohistochemistry and immunofluorescence assays were used to verify the bioinformatics results.
We determined that ferroptosis is prominently and specifically elevated in the glomerular compartment of LN patients compared to other forms of PCD and kidney disease. This finding was then verified by immunohistochemical staining of 4-HNE (a key indicator for ferroptosis) expression in our own cohort (P < 0.0001). Intercorrelation networks were observed between 4-HNE and blood urea nitrogen, SLE disease activity index, serum creatinine, and complement 4, and negatively correlated with glomerular filtration rate in our own LN cohort (P < 0.05). Furthermore, enhanced iron metabolism and reduced fatty acid synthesis may be the most important factors for ferroptosis within the glomerulus. Through analysis of a single cell sequencing dataset and verification of immunohistochemical and immunofluorescence staining, aberrantly activated lipid peroxidation in CD163+ macrophages and CD10+ PC+ (pyruvate carboxylase) epithelial cells indicated that they may be undergoing ferroptosis in the glomerular compartment.
Two dysregulated genes, CD163 and PC, were identified and verified that were significantly associated with lipid peroxidation. Targeting ferroptosis in CD163+ macrophages and CD10+ PC+ epithelial cells may provide novel therapeutic approaches in LN.
细胞死亡的失调和死亡细胞的清除缺陷与狼疮肾炎（LN）的发病机制密切相关。然而，最近发现的一种程序性细胞死亡（PCD）形式——铁死亡，其在 LN 中的作用尚未被详细探讨。本研究旨在探讨铁死亡及其相关代谢途径在 LN 发病机制中的作用。
通过平均每种 PCD 和途径中 z 分数变换的对数表达基因来计算复合基因表达分数。免疫组织化学和免疫荧光检测用于验证生物信息学结果。
我们确定与其他形式的 PCD 和肾脏疾病相比，铁死亡在 LN 患者的肾小球区室中显著且特异性升高。这一发现随后通过我们自己队列中 4-HNE（铁死亡的一个关键指标）表达的免疫组织化学染色得到验证（P<0.0001）。在我们自己的 LN 队列中，观察到 4-HNE 与血尿素氮、SLE 疾病活动指数、血清肌酐和补体 4 之间存在相互关联网络，与肾小球滤过率呈负相关（P<0.05）。此外，增强的铁代谢和减少的脂肪酸合成可能是肾小球内铁死亡的最重要因素。通过单细胞测序数据集的分析以及免疫组织化学和免疫荧光染色的验证，CD163+巨噬细胞和 CD10+PC+（丙酮酸羧化酶）上皮细胞中异常激活的脂质过氧化表明它们可能在肾小球区室中发生铁死亡。
鉴定并验证了两个与脂质过氧化显著相关的失调基因 CD163 和 PC。针对 CD163+巨噬细胞和 CD10+PC+上皮细胞中的铁死亡可能为 LN 提供新的治疗方法。
