Zhang Jinyu, Wang Yukai, Chen Chaoyi, Liu Xinran, Liu Xueqi, Wu Yonggui
Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, PR China.
Department of Nephropathy, The First Affiliated Hospital of Anhui Medical University, Hefei, Anhui 230022, PR China.
Int Immunopharmacol. 2025 Jan 10;144:113672. doi: 10.1016/j.intimp.2024.113672. Epub 2024 Nov 30.
Immunoglobulin A Nephropathy (IgAN) is a leading cause of end-stage renal disease (ESRD), but its pathogenesis remains unclear, and specific therapies are currently lacking. Consequently, identifying novel differentially expressed genes (DEGs) and therapeutic targets is of paramount importance to IgAN.
The Gene Expression Omnibus (GEO) databases GSE37460 and GSE104948, containing data from renal tissue of patients with IgAN and normal controls, were screened for DEGs, followed by enrichment pathway analysis. The potential key gene for IgAN, CD36, was identified through the single-cell sequencing dataset GSE166793 and histopathological analysis of patients with IgAN. Clinical and pathological data from patients with IgAN were collected to analyze the correlation between CD36 expression and various indicators in renal tissue, thereby evaluating the influence of CD36 on IgAN progression. The accuracy of the risk score model was assessed using receiver operating characteristic (ROC) curve analysis. Finally, CD36 expression was knocked down to explore its regulatory role in polymeric IgA1 (pIgA1)-stimulated mouse mesangial cells (MCs).
CD36 was identified as a key DEG from two GEO databases and a single-cell sequencing dataset. Compared to peritumoral normal tissues, CD36 expression levels were significantly increased in the IgAN group. Statistically significant differences were observed between M0 and M1, E0 and E1, S0 and S1, C0 and C1-2 in the updated Oxford Classification. CD36 expression showed positive correlations with 24-hour proteinuria, serum creatinine, and levels of fibrosis-related and autophagy-related factors in renal tissue. Additionally, CD36 and fibrosis-related factors were significantly elevated in MCs following pIgA1 stimulation. CD36 knockdown resulted in decreased extracellular matrix (ECM) accumulation in pIgA1-stimulated MCs. RNA-seq analysis of MCs with CD36 knockdown revealed significant alterations in autophagy and CD36 silencing restored autophagy levels in MCs treated with the autophagy inhibitor 3MA.
Our study confirmed that CD36 expression increases with the clinical progression of IgAN and CD36 knockdown alleviates MCs injury by inhibiting ECM accumulation and restoring autophagy.
免疫球蛋白A肾病（IgAN）是终末期肾病（ESRD）的主要病因，但其发病机制仍不清楚，目前缺乏特异性治疗方法。因此，鉴定新的差异表达基因（DEG）和治疗靶点对IgAN至关重要。
对包含IgAN患者肾组织和正常对照数据的基因表达综合数据库（GEO）GSE37460和GSE104948进行DEG筛选，随后进行富集通路分析。通过单细胞测序数据集GSE166793和IgAN患者的组织病理学分析鉴定IgAN的潜在关键基因CD36。收集IgAN患者的临床和病理数据，分析CD36表达与肾组织中各种指标的相关性，从而评估CD36对IgAN进展的影响。使用受试者工作特征（ROC）曲线分析评估风险评分模型的准确性。最后，敲低CD36表达以探讨其在多聚免疫球蛋白A1（pIgA1）刺激小鼠系膜细胞（MCs）中的调节作用。
CD36被鉴定为来自两个GEO数据库和一个单细胞测序数据集的关键DEG。与肿瘤旁正常组织相比，IgAN组中CD36表达水平显著升高。在更新的牛津分类中，M0与M1、E0与E1、S0与S1、C0与C1-2之间观察到统计学显著差异。CD36表达与24小时蛋白尿、血清肌酐以及肾组织中纤维化相关和自噬相关因子水平呈正相关。此外，pIgA1刺激后MCs中CD36和纤维化相关因子显著升高。CD36敲低导致pIgA1刺激的MCs中细胞外基质（ECM）积累减少。对敲低CD36的MCs进行RNA测序分析显示自噬有显著改变，并且CD36沉默恢复了用自噬抑制剂3MA处理的MCs中的自噬水平。
我们的研究证实CD36表达随IgAN临床进展而增加，并且CD36敲低通过抑制ECM积累和恢复自噬减轻MCs损伤。
