Proteomic profiling of IgA nephropathy reveals distinct molecular prognostic subtypes

Xizhao Chen; Mansheng Li; Songbiao Zhu; Yang Lu; Shuwei Duan; Xu Wang; Yong Wang; Pu Chen; Jie Wu; Di Wu; Zhe Feng; Guangyan Cai; Yunping Zhu; Haiteng Deng; Xiangmei Chen

doi:10.1016/j.isci.2023.105961

Proteomic profiling of IgA nephropathy reveals distinct molecular prognostic subtypes

iScience. 2023 Jan 13;26(3):105961. doi: 10.1016/j.isci.2023.105961. eCollection 2023 Mar 17.

Authors

Xizhao Chen¹, Mansheng Li², Songbiao Zhu³, Yang Lu¹, Shuwei Duan¹, Xu Wang¹, Yong Wang¹, Pu Chen¹, Jie Wu¹, Di Wu⁴, Zhe Feng¹, Guangyan Cai¹, Yunping Zhu², Haiteng Deng³, Xiangmei Chen¹

Affiliations

¹ 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.
² State Key Laboratory of Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Life Omics, Beijing 102206, China.
³ MOE Key Laboratory of Bioinformatics, Center for Synthetic and Systematic Biology, School of Life Sciences, Tsinghua University, Beijing 100084, China.
⁴ Department of Nephrology, Capital Medical University Electric Power Teaching Hospital, Beijing 100073, China.

Abstract

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.

Keywords: Immunology; Nephrology; Pathophysiology; Proteomics.