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

Xie Mengxiao; Wu Zhijiao; Ying Shuai; Liu Longfei; Zhao Chenhui; Yao Chunlei; Zhang Zhiwei; Luo Can; Wang Wenbo; Zhao Dan; Zhang Jing; Qiu Wen

doi:10.1038/s12276-021-00589-9

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자료유형: 학술저널

저자정보: Xie Mengxiao (Nanjing Medical University) Wu Zhijiao (Nanjing Medical University) Ying Shuai (Nanjing Medical University) Liu Longfei (Nanjing Medical University) Zhao Chenhui (Nanjing Medical University) Yao Chunlei (Nanjing Medical University) Zhang Zhiwei (Nanjing Medical University) Luo Can (Nanjing Medical University) Wang Wenbo (Nanjing Medical University) Zhao Dan (Nanjing Medical University) Zhang Jing (Nanjing Medical University) Qiu Wen (Nanjing Medical University)

저널정보: 대한생화학·분자생물학회 Experimental and Molecular Medicine Experimental and Molecular Medicine 제53권

발행연도: 2021.4

수록면: 1 - 19 (19page)

DOI: 10.1038/s12276-021-00589-9

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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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