Yu Leilin, Lin Wei, Shen Chanjuan, Meng Ting, Jin Peng, Ding Xiang, Eggenhuizen Peter J, Ooi Joshua D, Tang Rong, Nie Wannian, Li Xia, Xiao Xiangcheng, Zhong Yong
Department of Nephrology, Xiangya Hospital, Central South University, Changsha, China.
Jiujiang Traditional Medicine Hospital, Jiujiang, China.
Front Med (Lausanne). 2022 Jul 22;9:869284. doi: 10.3389/fmed.2022.869284. eCollection 2022.
To date, the pathogenesis of hepatitis B virus (HBV)-associated membranous nephropathy (MN) remains elusive. This study aimed to decipher the etiopathogenesis of HBV-associated MN by performing single-cell RNA sequencing (scRNA-seq) of kidney biopsy specimens from a patient with HBV-associated MN and two healthy individuals. We generated 4,114 intrarenal single-cell transcriptomes from the HBV-associated MN patient by scRNA-seq. Compared to healthy individuals, podocytes in the HBV-associated MN patient showed an increased expression of extracellular matrix formation-related genes, including , and . Kidney endothelial cells (ECs) in the HBV-associated MN were enriched in inflammatory pathways, including NF-kappa B signaling, IL-17 signaling, TNF signaling and NOD-like receptor signaling. Gene ontology (GO) functional enrichment analysis and Gene Set Variation Analysis (GSVA) further revealed that differentially expressed genes (DEGs) of ECs from the HBV-associated MN patients were enriched in apoptotic signaling pathway, response to cytokine and leukocyte cell-cell adhesion. The up-regulated DEGs in glomerular ECs of HBV-associated MN patients were involved in biological processes such as viral gene expression, and protein targeting to endoplasmic reticulum. We further verified that the overexpressed genes in ECs from HBV-associated MN were mainly enriched in regulation of protein targeting to endoplasmic reticulum, exocytosis, viral gene expression, IL-6 and IL-1 secretion when compared with anti-phospholipase A2 receptor (PLA2R)-positive idiopathic membranous nephropathy (IMN). The receptor-ligand crosstalk analysis revealed potential interactions between endothelial cells and other cells in HBV-associated-MN. These results offer new insight into the pathogenesis of HBV-associated MN and may identify new therapeutic targets for HBV-associated MN.
迄今为止，乙型肝炎病毒（HBV）相关性膜性肾病（MN）的发病机制仍不清楚。本研究旨在通过对一名HBV相关性MN患者和两名健康个体的肾活检标本进行单细胞RNA测序（scRNA-seq），来阐明HBV相关性MN的病因发病机制。我们通过scRNA-seq从HBV相关性MN患者中生成了4114个肾内单细胞转录组。与健康个体相比，HBV相关性MN患者的足细胞中细胞外基质形成相关基因的表达增加，包括 、 和 。HBV相关性MN中的肾内皮细胞（ECs）在包括核因子κB信号传导、白细胞介素-17信号传导、肿瘤坏死因子信号传导和NOD样受体信号传导等炎症途径中富集。基因本体（GO）功能富集分析和基因集变异分析（GSVA）进一步显示，HBV相关性MN患者的ECs中差异表达基因（DEGs）在凋亡信号通路、对细胞因子的反应和白细胞细胞间黏附中富集。HBV相关性MN患者肾小球ECs中上调的DEGs参与了病毒基因表达和蛋白质靶向内质网等生物学过程。我们进一步证实，与抗磷脂酶A2受体（PLA2R）阳性的特发性膜性肾病（IMN）相比，HBV相关性MN的ECs中过表达的基因主要富集在蛋白质靶向内质网的调控、胞吐作用、病毒基因表达、白细胞介素-6和白细胞介素-1分泌中。受体-配体相互作用分析揭示了HBV相关性MN中内皮细胞与其他细胞之间的潜在相互作用。这些结果为HBV相关性MN的发病机制提供了新的见解，并可能为HBV相关性MN确定新的治疗靶点。
