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.
复制标题
Sublytic C5b-9 通过增强大鼠 Thy-1 肾炎中的 Cyclin D1，通过 ERK1/2 依赖性 SOX9 磷酸化和乙酰化诱导肾小球系膜细胞增殖
DOI：
10.1038/s12276-021-00589-9
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发表时间：
2021-04
影响因子：
12.8
通讯作者：
Wang Y
中科院分区：
文献类型：
--
作者：
Xie M;Wu Z;Ying S;Liu L;Zhao C;Yao C;Zhang Z;Luo C;Wang W;Zhao D;Zhang J;Qiu W;Wang Y
肾小球系膜细胞（GMC）增殖是人系膜增生性肾小球肾炎（MsPGN）或MsPGN动物模型（例如大鼠Thy-1肾炎（Thy-1N）模型）中的组织病理学改变。尽管 GMC 膜上的亚裂解 C5b-9 组装可以触发细胞增殖，但其机制仍不清楚。我们发现，亚裂解性 C5b-9 诱导的大鼠 GMC 增殖是由细胞外信号调节激酶 1/2 (ERK1/2)、sry 相关的 HMG-box 9 (SOX9) 和 Cyclin D1 驱动的。在这里，ERK1/2磷酸化是由sublytic C5b-9激活的钙流入-PKC-α-Raf-MEK1/2轴的结果，并且ERK1/2依赖性SOX9与Cyclin D1启动子（−582至-238 nt）的结合增强了Cyclin D1基因转录。此外，ERK1/2不仅与细胞核中的SOX9相互作用，介导其在丝氨酸残基64（质谱鉴定的新位点）和181（已知位点）处的磷酸化，而且还通过提高通用控制非抑制蛋白5（GCN5）的表达间接诱导SOX9乙酰化，共同导致Cyclin D1合成和GMC增殖。此外，我们的体内实验证实，沉默这些基因可以改善 Thy-1N 大鼠的病变，并减少 SOX9 磷酸化、乙酰化和 Cyclin D1 的表达。此外，MsPGN患者的肾组织切片还显示ERK1/2、SOX9和Cyclin D1的磷酸化或表达较高。总之，这些发现表明，在大鼠 Thy-1N 中，亚裂解 C5b-9 诱导的 GMC 增殖需要通过增强的 Cyclin D1 基因转录来实现 SOX9 磷酸化和乙酰化，这可能为人类 MsPGN 发病机制提供新的见解。研究人员阐明了一种称为系膜增生性肾小球肾炎（MsPGN）的肾脏疾病背后的机制，这种疾病会导致某些肾细胞过度增殖。在 MsPGN 中，肾小球系膜细胞 (GMC) 过度增殖，导致肾脏损伤、功能下降和肾衰竭。分子水平的机制尚不清楚。中国南京医科大学的 Yingwei Wang 领导的团队利用大鼠动物模型研究了导致 GMC 增殖的原因。他们发现，通常与细胞增殖有关的转录因子蛋白 SOX9 被磷酸化和乙酰化，从而增强其转录活性，并使其能够激活控制细胞周期的其他分子，从而导致 GMC 过度增殖。阐明该动物模型的疾病机制可能有助于了解人类的疾病并确定治疗靶点。
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. Researchers have clarified the mechanism behind a kidney disease called mesangioproliferative glomerulonephritis (MsPGN), which causes certain kidney cells to overproliferate. In MsPGN, cells called glomerular mesangial cells (GMCs) overproliferate, causing kidney lesions, decreased function, and kidney failure. The mechanism at the molecular level has been unclear. A team led by Yingwei Wang at Nanjing Medical University in China investigated what leads GMCs to proliferate, using a rat animal model. They found that the transcription factor protein SOX9, often implicated in cell proliferation, is both phosphorylated and acetylated, enhancing its transcriptional activities and permitting it to activate other molecules that control the cell cycle, leading to overproliferation of GMCs. Elucidating the disease mechanism in this animal model may help to understand the disease in humans, and identify therapeutic targets.
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