Chen Xizhao, Li Mansheng, Zhu Songbiao, Lu Yang, Duan Shuwei, Wang Xu, Wang Yong, Chen Pu, Wu Jie, Wu Di, Feng Zhe, Cai Guangyan, Zhu Yunping, Deng Haiteng, Chen Xiangmei
Department of Nephrology, First Medical Center of Chinese PLA General Hospital, Nephrology Institute of the Chinese People's Liberation Army, State Key Laboratory of Kidney Diseases, National Clinical Research Center for Kidney Diseases, Beijing Key Laboratory of Kidney Disease Research, Beijing 100853, China.
State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Life Omics, Beijing 102206, China.
iScience. 2023 Jan 13;26(3):105961. doi: 10.1016/j.isci.2023.105961. eCollection 2023 Mar 17.
IgA nephropathy (IgAN) is a heterogeneous disease, which poses a series of challenges to accurate diagnosis and personalized therapy. Herein, we constructed a systematic quantitative proteome atlas from 59 IgAN and 19 normal control donors. Consensus sub-clustering of proteomic profiles divided IgAN into three subtypes (IgAN-C1, C2, and C3). IgAN-C2 had similar proteome expression patterns with normal control, while IgAN-C1/C3 exhibited higher level of complement activation, more severe mitochondrial injury, and significant extracellular matrix accumulation. Interestingly, the complement mitochondrial extracellular matrix (CME) pathway enrichment score achieved a high diagnostic power to distinguish IgAN-C2 from IgAN-C1/C3 (AUC>0.9). In addition, the proteins related to mesangial cells, endothelial cells, and tubular interstitial fibrosis were highly expressed in IgAN-C1/C3. Most critically, IgAN-C1/C3 had a worse prognosis compared to IgAN-C2 (30% eGFR decline, p = 0.02). Altogether, we proposed a molecular subtyping and prognostic system which could help to understand IgAN heterogeneity and improve the treatment in the clinic.
IgA 肾病（IgAN）是一种异质性疾病，对准确诊断和个性化治疗提出了一系列挑战。在此，我们构建了一个来自59例IgAN供体和19例正常对照供体的系统定量蛋白质组图谱。蛋白质组学图谱的一致性亚聚类将IgAN分为三个亚型（IgAN-C1、C2和C3）。IgAN-C2与正常对照具有相似的蛋白质组表达模式，而IgAN-C1/C3表现出更高水平的补体激活、更严重的线粒体损伤和显著的细胞外基质积累。有趣的是，补体-线粒体-细胞外基质（CME）途径富集评分在区分IgAN-C2与IgAN-C1/C3方面具有较高的诊断效能（AUC>0.9）。此外，与系膜细胞、内皮细胞和肾小管间质纤维化相关的蛋白质在IgAN-C1/C3中高表达。最关键的是，与IgAN-C2相比，IgAN-C1/C3的预后更差（估计肾小球滤过率下降30%，p = 0.02）。总之，我们提出了一种分子分型和预后系统，有助于理解IgAN的异质性并改善临床治疗。
