2. Academic Validation
  3. Sublytic C5b-9 induces glomerular mesangial cell proliferation via ERK1/2-dependent SOX9 phosphorylation and acetylation by enhancing Cyclin D1 in rat Thy-1 nephritis

Sublytic C5b-9 induces glomerular mesangial cell proliferation via ERK1/2-dependent SOX9 phosphorylation and acetylation by enhancing Cyclin D1 in rat Thy-1 nephritis

  • Exp Mol Med. 2021 Apr;53(4):572-590. doi: 10.1038/s12276-021-00589-9.
Mengxiao Xie 1 2,  Zhijiao Wu 1,  Shuai Ying 1,  Longfei Liu 1 3,  Chenhui Zhao 4,  Chunlei Yao 5,  Zhiwei Zhang 1,  Can Luo 1,  Wenbo Wang 1,  Dan Zhao 1,  Jing Zhang 1,  Wen Qiu 6 7,  Yingwei Wang 8 9
Affiliations

Affiliations

  • 1 Department of Immunology, and Key Laboratory of Immunological Environment and Disease, Nanjing Medical University, 101 Longmian Road, Nanjing, Jiangsu, 211166, China.
  • 2 Department of Laboratory Medicine, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China.
  • 3 Department of Central Laboratory, The Affiliated Huaian No. 1 People's Hospital, Nanjing Medical University, One West Huanghe Road, Huai'an, Jiangsu, 223300, China.
  • 4 Department of Oncology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China.
  • 5 Department of Nephrology, The First Affiliated Hospital of Nanjing Medical University, 300 Guangzhou Road, Nanjing, Jiangsu, 210029, China.
  • 6 Department of Immunology, and Key Laboratory of Immunological Environment and Disease, Nanjing Medical University, 101 Longmian Road, Nanjing, Jiangsu, 211166, China. qiuwen@njmu.edu.cn.
  • 7 Key Laboratory of Antibody Technology of Ministry of Health, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. qiuwen@njmu.edu.cn.
  • 8 Department of Immunology, and Key Laboratory of Immunological Environment and Disease, Nanjing Medical University, 101 Longmian Road, Nanjing, Jiangsu, 211166, China. wangyw1508@njmu.edu.cn.
  • 9 Key Laboratory of Antibody Technology of Ministry of Health, Nanjing Medical University, Nanjing, Jiangsu, 211166, China. wangyw1508@njmu.edu.cn.
PMID: 33811247 DOI: 10.1038/s12276-021-00589-9
Abstract

Glomerular mesangial cell (GMC) proliferation is a histopathological alteration in human mesangioproliferative glomerulonephritis (MsPGN) or in animal models of MsPGN, e.g., the rat Thy-1 nephritis (Thy-1N) model. Although sublytic C5b-9 assembly on the GMC membrane can trigger cell proliferation, the mechanisms are still undefined. We found that sublytic C5b-9-induced rat GMC proliferation was driven by extracellular signal-regulated kinase 1/2 (ERK1/2), sry-related HMG-box 9 (SOX9), and Cyclin D1. Here, ERK1/2 phosphorylation was a result of the calcium influx-PKC-α-Raf-MEK1/2 axis activated by sublytic C5b-9, and Cyclin D1 gene transcription was enhanced by ERK1/2-dependent SOX9 binding to the Cyclin D1 promoter (-582 to -238 nt). In addition, ERK1/2 not only interacted with SOX9 in the cell nucleus to mediate its phosphorylation at serine residues 64 (a new site identified by mass spectrometry) and 181 (a known site), but also indirectly induced SOX9 acetylation by elevating the expression of general control non-repressed protein 5 (GCN5), which together resulted in Cyclin D1 synthesis and GMC proliferation. Moreover, our in vivo experiments confirmed that silencing these genes ameliorated the lesions of Thy-1N rats and reduced SOX9 phosphorylation, acetylation and Cyclin D1 expression. Furthermore, the renal tissue sections of MsPGN patients also showed higher phosphorylation or expression of ERK1/2, SOX9, and Cyclin D1. In summary, these findings suggest that sublytic C5b-9-induced GMC proliferation in rat Thy-1N requires SOX9 phosphorylation and acetylation via enhanced Cyclin D1 gene transcription, which may provide a new insight into human MsPGN pathogenesis.

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